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Stop using radiation therapy in older women, expert says
MIAMI BEACH – The use of radiation therapy should be decreased in women at low risk of local recurrence of breast cancer, Dr. Kevin S. Hughes said at the annual Miami Breast Cancer Conference.
This is particularly true for women aged 70 years and older with clinical stage 1, estrogen receptor–positive cancers, but may also apply to younger women with low recurrence risk, Dr. Hughes, codirector of the Avon Comprehensive Breast Cancer Evaluation Center at Massachusetts General Hospital, Boston, said at the conference, held by Physicians’ Education Resource.
Older women have lower-risk breast cancers that are more responsive to hormonal treatments, he explained, noting that Cancer and Leukemia Group B protocol 9343 showed that radiation therapy provides little benefit among older women; the 10-year recurrence of 9% in those treated with conservation and radiation therapy was similar to the recurrence rate among women under age 40 years, and to the unilateral cancer risk of a patient with lobular carcinoma in situ.
No difference was seen in ultimate breast preservation, distant disease-free survival, or survival in those with vs. without radiation therapy, he said.
In fact, 94% of patients who died at the time of 12-year follow-up died of something other than breast cancer, he noted.
Despite efforts over the years to publicize these and similar findings, the use of radiation therapy in this population has not declined substantially.
“It is important to stop using radiation in older women who don’t benefit from this therapy and don’t really need it,” he stressed.
As for younger women, the PRIME II trial showed similar results in 658 women aged 65 years and older, and the PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission) trial will look at women aged 50-75 years with stage 1, ER+ cancer who are at low risk of recurrence, Dr. Hughes said.
In PRIME II, postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment provided some reduction in the local recurrence at 5-year follow-up, but the investigators concluded that the rate of ipsilateral breast tumor recurrence “is probably low enough for omission of radiotherapy to be considered for some patients (Lancet. 2015;16[3]:266-73).
The findings in older women are clear with the respect to the need for avoiding radiation therapy in those with low local recurrence risk, and the findings in younger women are promising, he concluded.
Dr. Hughes is on the speakers bureau for Myriad Genetics, is a shareholder of the healthcare IT company 5AM Solutions, and is the founder (with a financial interest) of Hughes Risk Apps, LLC.
MIAMI BEACH – The use of radiation therapy should be decreased in women at low risk of local recurrence of breast cancer, Dr. Kevin S. Hughes said at the annual Miami Breast Cancer Conference.
This is particularly true for women aged 70 years and older with clinical stage 1, estrogen receptor–positive cancers, but may also apply to younger women with low recurrence risk, Dr. Hughes, codirector of the Avon Comprehensive Breast Cancer Evaluation Center at Massachusetts General Hospital, Boston, said at the conference, held by Physicians’ Education Resource.
Older women have lower-risk breast cancers that are more responsive to hormonal treatments, he explained, noting that Cancer and Leukemia Group B protocol 9343 showed that radiation therapy provides little benefit among older women; the 10-year recurrence of 9% in those treated with conservation and radiation therapy was similar to the recurrence rate among women under age 40 years, and to the unilateral cancer risk of a patient with lobular carcinoma in situ.
No difference was seen in ultimate breast preservation, distant disease-free survival, or survival in those with vs. without radiation therapy, he said.
In fact, 94% of patients who died at the time of 12-year follow-up died of something other than breast cancer, he noted.
Despite efforts over the years to publicize these and similar findings, the use of radiation therapy in this population has not declined substantially.
“It is important to stop using radiation in older women who don’t benefit from this therapy and don’t really need it,” he stressed.
As for younger women, the PRIME II trial showed similar results in 658 women aged 65 years and older, and the PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission) trial will look at women aged 50-75 years with stage 1, ER+ cancer who are at low risk of recurrence, Dr. Hughes said.
In PRIME II, postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment provided some reduction in the local recurrence at 5-year follow-up, but the investigators concluded that the rate of ipsilateral breast tumor recurrence “is probably low enough for omission of radiotherapy to be considered for some patients (Lancet. 2015;16[3]:266-73).
The findings in older women are clear with the respect to the need for avoiding radiation therapy in those with low local recurrence risk, and the findings in younger women are promising, he concluded.
Dr. Hughes is on the speakers bureau for Myriad Genetics, is a shareholder of the healthcare IT company 5AM Solutions, and is the founder (with a financial interest) of Hughes Risk Apps, LLC.
MIAMI BEACH – The use of radiation therapy should be decreased in women at low risk of local recurrence of breast cancer, Dr. Kevin S. Hughes said at the annual Miami Breast Cancer Conference.
This is particularly true for women aged 70 years and older with clinical stage 1, estrogen receptor–positive cancers, but may also apply to younger women with low recurrence risk, Dr. Hughes, codirector of the Avon Comprehensive Breast Cancer Evaluation Center at Massachusetts General Hospital, Boston, said at the conference, held by Physicians’ Education Resource.
Older women have lower-risk breast cancers that are more responsive to hormonal treatments, he explained, noting that Cancer and Leukemia Group B protocol 9343 showed that radiation therapy provides little benefit among older women; the 10-year recurrence of 9% in those treated with conservation and radiation therapy was similar to the recurrence rate among women under age 40 years, and to the unilateral cancer risk of a patient with lobular carcinoma in situ.
No difference was seen in ultimate breast preservation, distant disease-free survival, or survival in those with vs. without radiation therapy, he said.
In fact, 94% of patients who died at the time of 12-year follow-up died of something other than breast cancer, he noted.
Despite efforts over the years to publicize these and similar findings, the use of radiation therapy in this population has not declined substantially.
“It is important to stop using radiation in older women who don’t benefit from this therapy and don’t really need it,” he stressed.
As for younger women, the PRIME II trial showed similar results in 658 women aged 65 years and older, and the PRECISION (Profiling Early Breast Cancer for Radiotherapy Omission) trial will look at women aged 50-75 years with stage 1, ER+ cancer who are at low risk of recurrence, Dr. Hughes said.
In PRIME II, postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment provided some reduction in the local recurrence at 5-year follow-up, but the investigators concluded that the rate of ipsilateral breast tumor recurrence “is probably low enough for omission of radiotherapy to be considered for some patients (Lancet. 2015;16[3]:266-73).
The findings in older women are clear with the respect to the need for avoiding radiation therapy in those with low local recurrence risk, and the findings in younger women are promising, he concluded.
Dr. Hughes is on the speakers bureau for Myriad Genetics, is a shareholder of the healthcare IT company 5AM Solutions, and is the founder (with a financial interest) of Hughes Risk Apps, LLC.
EXPERT ANALYSIS FROM MBCC
Neoadjuvant chemo reduces extent of axillary dissection in some breast cancers
BOSTON – The majority of patients with hormone receptor–negative breast cancer in the United States get chemotherapy in the adjuvant setting, but neoadjuvant chemotherapy is gaining in use, and is associated with a higher likelihood of breast-conserving surgery for some women with advanced disease, as well as less extensive axillary node dissection.
A review of data on more than 130,000 patients with breast tumors negative for both estrogen and progesterone receptors (ER–/PR–) showed that among patients with clinical stage T3 disease, 26% of those who had received neoadjuvant chemotherapy were able to have breast-conserving surgery, compared with 20% of patients who had received adjuvant chemotherapy, reported Dr. Carlos A. Puig and his colleagues from the Mayo Clinic in Rochester, Minn.
“Patients treated with neoadjuvant chemotherapy have less extensive axillary surgery and a lower rate of nodal positivity,” he added at the annual Society of Surgical Oncology Cancer Symposium.
The data showed that nearly a third of all patients with clinically node-positive disease (cN1-3) who received neoadjuvant chemotherapy had pathologically node-negative disease at the end of therapy.
The aggressive biology of ER–/PR– tumors makes them suitable targets for chemotherapy in the neoadjuvant setting, Dr. Puig said. Overall survival among patients with ER–/PR– who receive neoadjuvant chemotherapy is comparable to that of patients who receive chemotherapy in the adjuvant setting. Neoadjuvant regimens can also downstage tumors before surgery, and a pathologic complete response to chemotherapy delivered prior to surgery is prognostic for outcomes.
Trends in chemotherapy
Dr. Puig and his colleagues combed through the National Cancer Data Base, looking for trends in national practice patterns of use of neoadjuvant chemotherapy in ER–/PR– breast cancer from 2004 through 2012.
They identified a total of 108,128 patients with invasive ER–/PR– breast cancer who received adjuvant chemotherapy, and 24,848 who received neoadjuvant chemo; an additional 43,969 patients who did not receive chemotherapy were excluded from the analysis.
Factors significantly associated with the choice to administer neoadjuvant chemotherapy included age younger than 50, no comorbidities vs. one or two comorbidities on the Charlson/Deyo index, academic/research center vs. community cancer program, higher clinical T stage, and higher clinical N stage.
There was a gradual increase in the use of neoadjuvant chemotherapy over time, from 14.2% in 2004 to 22.3% of all patients in 2012 (P less than .001).
The overall breast-conserving surgery rates were lower among patients who had chemotherapy in the neoadjuvant setting – 33.2% vs. 54.7% (P less than .001). The rates of conservative surgery increased over time, from 32% in 2004 to 36% in 2012 (P less than .001), but decreased over the same period in patients who had adjuvant chemotherapy, from 58% to 51%, respectively.
In a breakdown of surgery type by clinical T stage, mastectomy was more frequently performed in patients who had undergone neoadjuvant treatment, compared with adjuvant therapy, except for stage T3 disease. A higher percentage of those with T3 tumors who had neoadjuvant therapy had breast-conserving surgery in comparison with women who had T3 tumors and adjuvant therapy (26.2% vs. 20.2%, respectively; P less than .001).
To identify the extent of axillary surgery, the authors considered one to five nodes removed to be a surrogate for sentinel lymph node biopsy, and six or more nodes as a surrogate for axillary lymph node dissection.
They found that among patients with clinical stage N1 through N3 who received neoadjuvant chemotherapy, 31.8% converted to pathologically node-negative status.
Dr. Puig noted that the study was limited by the retrospective design and the lack of data on HER2 receptor status, making it impossible to distinguish between ER–/PR– and triple-negative tumors. In addition, they did not have data on genetic testing that could affect surgical choices, such as the presence of BRCA1 or BRCA2.
Following Dr. Puig’s presentation, Dr. Monica Morrow, chief of breast surgery at Memorial Sloan-Kettering Cancer Center, New York, commented that the study put together “patients in whom we would consider there to be an absolute indication for neoadjuvant chemotherapy – meaning T4, N2-N3 – and patients where it’s optional.” The study results suggested that not all patients who should receive neoadjuvant therapy were getting it “which is a little disturbing,” Dr. Morrow said.
She also noted that the decrease in the use of axillary lymph node dissection began prior to publication of studies suggesting that it might be safe to do so.
Dr. Puig and Dr. Morrow had no relevant disclosures.
BOSTON – The majority of patients with hormone receptor–negative breast cancer in the United States get chemotherapy in the adjuvant setting, but neoadjuvant chemotherapy is gaining in use, and is associated with a higher likelihood of breast-conserving surgery for some women with advanced disease, as well as less extensive axillary node dissection.
A review of data on more than 130,000 patients with breast tumors negative for both estrogen and progesterone receptors (ER–/PR–) showed that among patients with clinical stage T3 disease, 26% of those who had received neoadjuvant chemotherapy were able to have breast-conserving surgery, compared with 20% of patients who had received adjuvant chemotherapy, reported Dr. Carlos A. Puig and his colleagues from the Mayo Clinic in Rochester, Minn.
“Patients treated with neoadjuvant chemotherapy have less extensive axillary surgery and a lower rate of nodal positivity,” he added at the annual Society of Surgical Oncology Cancer Symposium.
The data showed that nearly a third of all patients with clinically node-positive disease (cN1-3) who received neoadjuvant chemotherapy had pathologically node-negative disease at the end of therapy.
The aggressive biology of ER–/PR– tumors makes them suitable targets for chemotherapy in the neoadjuvant setting, Dr. Puig said. Overall survival among patients with ER–/PR– who receive neoadjuvant chemotherapy is comparable to that of patients who receive chemotherapy in the adjuvant setting. Neoadjuvant regimens can also downstage tumors before surgery, and a pathologic complete response to chemotherapy delivered prior to surgery is prognostic for outcomes.
Trends in chemotherapy
Dr. Puig and his colleagues combed through the National Cancer Data Base, looking for trends in national practice patterns of use of neoadjuvant chemotherapy in ER–/PR– breast cancer from 2004 through 2012.
They identified a total of 108,128 patients with invasive ER–/PR– breast cancer who received adjuvant chemotherapy, and 24,848 who received neoadjuvant chemo; an additional 43,969 patients who did not receive chemotherapy were excluded from the analysis.
Factors significantly associated with the choice to administer neoadjuvant chemotherapy included age younger than 50, no comorbidities vs. one or two comorbidities on the Charlson/Deyo index, academic/research center vs. community cancer program, higher clinical T stage, and higher clinical N stage.
There was a gradual increase in the use of neoadjuvant chemotherapy over time, from 14.2% in 2004 to 22.3% of all patients in 2012 (P less than .001).
The overall breast-conserving surgery rates were lower among patients who had chemotherapy in the neoadjuvant setting – 33.2% vs. 54.7% (P less than .001). The rates of conservative surgery increased over time, from 32% in 2004 to 36% in 2012 (P less than .001), but decreased over the same period in patients who had adjuvant chemotherapy, from 58% to 51%, respectively.
In a breakdown of surgery type by clinical T stage, mastectomy was more frequently performed in patients who had undergone neoadjuvant treatment, compared with adjuvant therapy, except for stage T3 disease. A higher percentage of those with T3 tumors who had neoadjuvant therapy had breast-conserving surgery in comparison with women who had T3 tumors and adjuvant therapy (26.2% vs. 20.2%, respectively; P less than .001).
To identify the extent of axillary surgery, the authors considered one to five nodes removed to be a surrogate for sentinel lymph node biopsy, and six or more nodes as a surrogate for axillary lymph node dissection.
They found that among patients with clinical stage N1 through N3 who received neoadjuvant chemotherapy, 31.8% converted to pathologically node-negative status.
Dr. Puig noted that the study was limited by the retrospective design and the lack of data on HER2 receptor status, making it impossible to distinguish between ER–/PR– and triple-negative tumors. In addition, they did not have data on genetic testing that could affect surgical choices, such as the presence of BRCA1 or BRCA2.
Following Dr. Puig’s presentation, Dr. Monica Morrow, chief of breast surgery at Memorial Sloan-Kettering Cancer Center, New York, commented that the study put together “patients in whom we would consider there to be an absolute indication for neoadjuvant chemotherapy – meaning T4, N2-N3 – and patients where it’s optional.” The study results suggested that not all patients who should receive neoadjuvant therapy were getting it “which is a little disturbing,” Dr. Morrow said.
She also noted that the decrease in the use of axillary lymph node dissection began prior to publication of studies suggesting that it might be safe to do so.
Dr. Puig and Dr. Morrow had no relevant disclosures.
BOSTON – The majority of patients with hormone receptor–negative breast cancer in the United States get chemotherapy in the adjuvant setting, but neoadjuvant chemotherapy is gaining in use, and is associated with a higher likelihood of breast-conserving surgery for some women with advanced disease, as well as less extensive axillary node dissection.
A review of data on more than 130,000 patients with breast tumors negative for both estrogen and progesterone receptors (ER–/PR–) showed that among patients with clinical stage T3 disease, 26% of those who had received neoadjuvant chemotherapy were able to have breast-conserving surgery, compared with 20% of patients who had received adjuvant chemotherapy, reported Dr. Carlos A. Puig and his colleagues from the Mayo Clinic in Rochester, Minn.
“Patients treated with neoadjuvant chemotherapy have less extensive axillary surgery and a lower rate of nodal positivity,” he added at the annual Society of Surgical Oncology Cancer Symposium.
The data showed that nearly a third of all patients with clinically node-positive disease (cN1-3) who received neoadjuvant chemotherapy had pathologically node-negative disease at the end of therapy.
The aggressive biology of ER–/PR– tumors makes them suitable targets for chemotherapy in the neoadjuvant setting, Dr. Puig said. Overall survival among patients with ER–/PR– who receive neoadjuvant chemotherapy is comparable to that of patients who receive chemotherapy in the adjuvant setting. Neoadjuvant regimens can also downstage tumors before surgery, and a pathologic complete response to chemotherapy delivered prior to surgery is prognostic for outcomes.
Trends in chemotherapy
Dr. Puig and his colleagues combed through the National Cancer Data Base, looking for trends in national practice patterns of use of neoadjuvant chemotherapy in ER–/PR– breast cancer from 2004 through 2012.
They identified a total of 108,128 patients with invasive ER–/PR– breast cancer who received adjuvant chemotherapy, and 24,848 who received neoadjuvant chemo; an additional 43,969 patients who did not receive chemotherapy were excluded from the analysis.
Factors significantly associated with the choice to administer neoadjuvant chemotherapy included age younger than 50, no comorbidities vs. one or two comorbidities on the Charlson/Deyo index, academic/research center vs. community cancer program, higher clinical T stage, and higher clinical N stage.
There was a gradual increase in the use of neoadjuvant chemotherapy over time, from 14.2% in 2004 to 22.3% of all patients in 2012 (P less than .001).
The overall breast-conserving surgery rates were lower among patients who had chemotherapy in the neoadjuvant setting – 33.2% vs. 54.7% (P less than .001). The rates of conservative surgery increased over time, from 32% in 2004 to 36% in 2012 (P less than .001), but decreased over the same period in patients who had adjuvant chemotherapy, from 58% to 51%, respectively.
In a breakdown of surgery type by clinical T stage, mastectomy was more frequently performed in patients who had undergone neoadjuvant treatment, compared with adjuvant therapy, except for stage T3 disease. A higher percentage of those with T3 tumors who had neoadjuvant therapy had breast-conserving surgery in comparison with women who had T3 tumors and adjuvant therapy (26.2% vs. 20.2%, respectively; P less than .001).
To identify the extent of axillary surgery, the authors considered one to five nodes removed to be a surrogate for sentinel lymph node biopsy, and six or more nodes as a surrogate for axillary lymph node dissection.
They found that among patients with clinical stage N1 through N3 who received neoadjuvant chemotherapy, 31.8% converted to pathologically node-negative status.
Dr. Puig noted that the study was limited by the retrospective design and the lack of data on HER2 receptor status, making it impossible to distinguish between ER–/PR– and triple-negative tumors. In addition, they did not have data on genetic testing that could affect surgical choices, such as the presence of BRCA1 or BRCA2.
Following Dr. Puig’s presentation, Dr. Monica Morrow, chief of breast surgery at Memorial Sloan-Kettering Cancer Center, New York, commented that the study put together “patients in whom we would consider there to be an absolute indication for neoadjuvant chemotherapy – meaning T4, N2-N3 – and patients where it’s optional.” The study results suggested that not all patients who should receive neoadjuvant therapy were getting it “which is a little disturbing,” Dr. Morrow said.
She also noted that the decrease in the use of axillary lymph node dissection began prior to publication of studies suggesting that it might be safe to do so.
Dr. Puig and Dr. Morrow had no relevant disclosures.
Key clinical point: Neoadjuvant chemotherapy can benefit some patients with advanced hormone receptor–negative breast cancer.
Major finding: Among patients with cT3 disease, 26% who had neoadjuvant chemotherapy were able to have breast-conserving surgery, compared with 20% of patients who had received adjuvant chemotherapy.
Data source: Retrospective review of data on 132,976 patients with invasive ER–/PR– breast cancer.
Disclosures: Dr. Puig and Dr. Morrow had no relevant disclosures.
VIDEO: Focused breast cancer radiation maintains efficacy, cuts AEs
AMSTERDAM – Modifying the standard radiation dosage to women with early-stage breast cancer so that the tumor-bed dosage remained the same but eliminated the dosage delivered to surrounding breast tissue led to similar 5-year efficacy and reduced adverse effects in a multicenter U.K. trial that involved more than 2,000 patients.
“Partial-breast radiotherapy was noninferior to whole-breast radiotherpy for reducing local recurrences and reduced the severity of overall breast appearance and breast hardness,” Dr. Charlotte Coles said at the European Breast Cancer Congress. “I consider this practice changing,” concluded Dr. Coles of Cambridge (England) University Hospitals.
While some experts at the meeting agreed with Dr. Coles’ assessment of the findings, others took a more skeptical view, focusing on the median follow-up of just 5 years.
“There is still some question about the long-term results for local recurrence rates,” said Dr. Robert Mansel, professor of surgical oncology at Cardiff (Wales) University. In addition, “the rationale for doing this is to reduce side effects to the whole breast, but the results showed little difference in side effects” between women who received the standard radiation dosage and those who received a reduced dosage, “so the rationale for doing this is not quite there,” said Dr. Mansel, the session’s designated discussant.
The Intensity Modulated Partial Breast Radiotherapy for Women with Early Breast Cancer (IMPORT LOW) trial enrolled 2,018 patients with early breast cancer at 30 U.K. centers during 2007-2010. Patients underwent breast conservation surgery and were at least 50 years old, had a tumor of 3 cm or less, had an invasive and unifocal adenocarcinoma that was grade I, II, or III, and had lymph nodes that were either negative or had micrometastases (pN0 or pN1). The trial randomized these women to either standard, whole-breast radiation with 40 gray, a reduced-dosage regimen that delivered 40 gray to the tumor bed but 36 gray to the rest of the breast, or a partial regimen that delivered 40 gray to the tumor bed and no radiation at all to the rest of the ipsilateral breast. All three regimens were administered as 15 fractions.
After a median follow-up of 71 months, the 674 women randomized to the reduced regimen had a 26% reduction in their absolute local recurrence rate compared with the 674 whole-breast controls. The 670 women randomized to the partial regimen had an absolute reduction of 39%. Both of these relative reductions were statistically significant. These efficacy results also met the study’s prespecified primary endpoint for noninferiority for controlling local recurrences in the ipsilateral breast, Dr. Coles reported.
For the study’s secondary endpoints of various measures of adverse effects to the normal breast tissue, the partial-dosage regimen led to a statistically significant reduction in patient assessment of changed breast appearance (P = .005) and a reduced rate of patient perception of increased breast firmness (P = .001). The adverse-effects endpoints also showed a significant reduction with the partial regimen in physician assessment of breast edema (P = .0053). The overall rate of patients free of any adverse effect in their normal breast tissue after 5 years was 72% in the control patients, 79% in those who received the reduced-dose regimen (P = .042), and 81% in those who received the partial dose (P = .004).
An expert panel is scheduled to review new evidence on breast radiotherapy later in March, and these new data may produce a change in the recommended irradiation protocol, Dr. Coles said.
On Twitter @mitchelzoler
I believe that these 5-year results are sufficient to make the partial-dose radiation regimen our new standard treatment. The advantage is to better spare the normal breast tissue from radiation damage while maintaining similar local control compared with standard radiotherapy that irradiates the entire breast.
In the results reported by Dr. Coles, partial breast irradiation produced excellent local control with more limited toxicity. It should be used for women with an early, small, low-risk breast cancer detected by screening with no or very limited lymph node metastases. I estimate that about a third of women with breast cancer fall into this category. There seems to be no reason to not apply these findings to any woman who meets the enrollment criteria for the study.
One limitation of this study is that it involved a median 5-year follow-up, whereas we usually focus on 10-year follow-up data. However, we know that local-recurrence rates are usually low during years 6-10 following breast irradiation for these types of patients, so I think the 5-year data are sufficient.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Emiel J.T. Rutgers is a surgical oncologist and clinical director of the Netherlands Cancer Institute in Amsterdam. He had no disclosures. He made these comments during an interview.
I believe that these 5-year results are sufficient to make the partial-dose radiation regimen our new standard treatment. The advantage is to better spare the normal breast tissue from radiation damage while maintaining similar local control compared with standard radiotherapy that irradiates the entire breast.
In the results reported by Dr. Coles, partial breast irradiation produced excellent local control with more limited toxicity. It should be used for women with an early, small, low-risk breast cancer detected by screening with no or very limited lymph node metastases. I estimate that about a third of women with breast cancer fall into this category. There seems to be no reason to not apply these findings to any woman who meets the enrollment criteria for the study.
One limitation of this study is that it involved a median 5-year follow-up, whereas we usually focus on 10-year follow-up data. However, we know that local-recurrence rates are usually low during years 6-10 following breast irradiation for these types of patients, so I think the 5-year data are sufficient.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Emiel J.T. Rutgers is a surgical oncologist and clinical director of the Netherlands Cancer Institute in Amsterdam. He had no disclosures. He made these comments during an interview.
I believe that these 5-year results are sufficient to make the partial-dose radiation regimen our new standard treatment. The advantage is to better spare the normal breast tissue from radiation damage while maintaining similar local control compared with standard radiotherapy that irradiates the entire breast.
In the results reported by Dr. Coles, partial breast irradiation produced excellent local control with more limited toxicity. It should be used for women with an early, small, low-risk breast cancer detected by screening with no or very limited lymph node metastases. I estimate that about a third of women with breast cancer fall into this category. There seems to be no reason to not apply these findings to any woman who meets the enrollment criteria for the study.
One limitation of this study is that it involved a median 5-year follow-up, whereas we usually focus on 10-year follow-up data. However, we know that local-recurrence rates are usually low during years 6-10 following breast irradiation for these types of patients, so I think the 5-year data are sufficient.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Emiel J.T. Rutgers is a surgical oncologist and clinical director of the Netherlands Cancer Institute in Amsterdam. He had no disclosures. He made these comments during an interview.
AMSTERDAM – Modifying the standard radiation dosage to women with early-stage breast cancer so that the tumor-bed dosage remained the same but eliminated the dosage delivered to surrounding breast tissue led to similar 5-year efficacy and reduced adverse effects in a multicenter U.K. trial that involved more than 2,000 patients.
“Partial-breast radiotherapy was noninferior to whole-breast radiotherpy for reducing local recurrences and reduced the severity of overall breast appearance and breast hardness,” Dr. Charlotte Coles said at the European Breast Cancer Congress. “I consider this practice changing,” concluded Dr. Coles of Cambridge (England) University Hospitals.
While some experts at the meeting agreed with Dr. Coles’ assessment of the findings, others took a more skeptical view, focusing on the median follow-up of just 5 years.
“There is still some question about the long-term results for local recurrence rates,” said Dr. Robert Mansel, professor of surgical oncology at Cardiff (Wales) University. In addition, “the rationale for doing this is to reduce side effects to the whole breast, but the results showed little difference in side effects” between women who received the standard radiation dosage and those who received a reduced dosage, “so the rationale for doing this is not quite there,” said Dr. Mansel, the session’s designated discussant.
The Intensity Modulated Partial Breast Radiotherapy for Women with Early Breast Cancer (IMPORT LOW) trial enrolled 2,018 patients with early breast cancer at 30 U.K. centers during 2007-2010. Patients underwent breast conservation surgery and were at least 50 years old, had a tumor of 3 cm or less, had an invasive and unifocal adenocarcinoma that was grade I, II, or III, and had lymph nodes that were either negative or had micrometastases (pN0 or pN1). The trial randomized these women to either standard, whole-breast radiation with 40 gray, a reduced-dosage regimen that delivered 40 gray to the tumor bed but 36 gray to the rest of the breast, or a partial regimen that delivered 40 gray to the tumor bed and no radiation at all to the rest of the ipsilateral breast. All three regimens were administered as 15 fractions.
After a median follow-up of 71 months, the 674 women randomized to the reduced regimen had a 26% reduction in their absolute local recurrence rate compared with the 674 whole-breast controls. The 670 women randomized to the partial regimen had an absolute reduction of 39%. Both of these relative reductions were statistically significant. These efficacy results also met the study’s prespecified primary endpoint for noninferiority for controlling local recurrences in the ipsilateral breast, Dr. Coles reported.
For the study’s secondary endpoints of various measures of adverse effects to the normal breast tissue, the partial-dosage regimen led to a statistically significant reduction in patient assessment of changed breast appearance (P = .005) and a reduced rate of patient perception of increased breast firmness (P = .001). The adverse-effects endpoints also showed a significant reduction with the partial regimen in physician assessment of breast edema (P = .0053). The overall rate of patients free of any adverse effect in their normal breast tissue after 5 years was 72% in the control patients, 79% in those who received the reduced-dose regimen (P = .042), and 81% in those who received the partial dose (P = .004).
An expert panel is scheduled to review new evidence on breast radiotherapy later in March, and these new data may produce a change in the recommended irradiation protocol, Dr. Coles said.
On Twitter @mitchelzoler
AMSTERDAM – Modifying the standard radiation dosage to women with early-stage breast cancer so that the tumor-bed dosage remained the same but eliminated the dosage delivered to surrounding breast tissue led to similar 5-year efficacy and reduced adverse effects in a multicenter U.K. trial that involved more than 2,000 patients.
“Partial-breast radiotherapy was noninferior to whole-breast radiotherpy for reducing local recurrences and reduced the severity of overall breast appearance and breast hardness,” Dr. Charlotte Coles said at the European Breast Cancer Congress. “I consider this practice changing,” concluded Dr. Coles of Cambridge (England) University Hospitals.
While some experts at the meeting agreed with Dr. Coles’ assessment of the findings, others took a more skeptical view, focusing on the median follow-up of just 5 years.
“There is still some question about the long-term results for local recurrence rates,” said Dr. Robert Mansel, professor of surgical oncology at Cardiff (Wales) University. In addition, “the rationale for doing this is to reduce side effects to the whole breast, but the results showed little difference in side effects” between women who received the standard radiation dosage and those who received a reduced dosage, “so the rationale for doing this is not quite there,” said Dr. Mansel, the session’s designated discussant.
The Intensity Modulated Partial Breast Radiotherapy for Women with Early Breast Cancer (IMPORT LOW) trial enrolled 2,018 patients with early breast cancer at 30 U.K. centers during 2007-2010. Patients underwent breast conservation surgery and were at least 50 years old, had a tumor of 3 cm or less, had an invasive and unifocal adenocarcinoma that was grade I, II, or III, and had lymph nodes that were either negative or had micrometastases (pN0 or pN1). The trial randomized these women to either standard, whole-breast radiation with 40 gray, a reduced-dosage regimen that delivered 40 gray to the tumor bed but 36 gray to the rest of the breast, or a partial regimen that delivered 40 gray to the tumor bed and no radiation at all to the rest of the ipsilateral breast. All three regimens were administered as 15 fractions.
After a median follow-up of 71 months, the 674 women randomized to the reduced regimen had a 26% reduction in their absolute local recurrence rate compared with the 674 whole-breast controls. The 670 women randomized to the partial regimen had an absolute reduction of 39%. Both of these relative reductions were statistically significant. These efficacy results also met the study’s prespecified primary endpoint for noninferiority for controlling local recurrences in the ipsilateral breast, Dr. Coles reported.
For the study’s secondary endpoints of various measures of adverse effects to the normal breast tissue, the partial-dosage regimen led to a statistically significant reduction in patient assessment of changed breast appearance (P = .005) and a reduced rate of patient perception of increased breast firmness (P = .001). The adverse-effects endpoints also showed a significant reduction with the partial regimen in physician assessment of breast edema (P = .0053). The overall rate of patients free of any adverse effect in their normal breast tissue after 5 years was 72% in the control patients, 79% in those who received the reduced-dose regimen (P = .042), and 81% in those who received the partial dose (P = .004).
An expert panel is scheduled to review new evidence on breast radiotherapy later in March, and these new data may produce a change in the recommended irradiation protocol, Dr. Coles said.
On Twitter @mitchelzoler
AT EBCC 10
Key clinical point: Maintaining the standard breast cancer radiation dosage to the tumor bed while eliminating the dosage to the rest of the breast maintained efficacy and improved posttreatment breast appearance.
Major finding: Women not receiving radiation to their normal breast tissue had a 39% reduction in local recurrences, compared with controls.
Data source: The IMPORT LOW study, which randomized 2,018 women with early breast cancer at 30 U.K. centers for a median of 5 years.
Disclosures: IMPORT LOW received no commercial support. Dr. Coles and Dr. Mansel has no disclosures.
Ultrasound bested tomosynthesis for screening dense breast tissue
Ultrasound was about 1.8 times more sensitive than tomosynthesis for the incremental detection of breast cancer in women with radiologically dense breasts and negative two-dimensional mammography screening, according to interim results from the first prospective trial to directly compare the two modalities.
“However, future application of adjunct screening should consider that tomosynthesis detected more than 50% of the additional breast cancers in these women, and could potentially be [a] primary screening modality,” wrote Dr. Alberto Tagliafico of the University of Genoa (Italy) and his associates. The study was published online March 9 in the Journal of Clinical Oncology and presented simultaneously at the European Breast Cancer Conference.
Radiologically dense breast tissue undermines the sensitivity of mammography and is itself an independent risk factor for breast cancer. Recently, many states began requiring that women be informed of their breast density and adjunct screening measures, such as ultrasound. But estimates of the sensitivity of ultrasound have ranged from about 1.9 to 4.2 cancers for every 1,000 screens, said the researchers. This variance, combined with costs and concerns about false-positive recalls, have fueled debates about the value of adjunct measures in breast cancer screening, they added. To help clarify these issues, the multicenter ASTOUND (Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts) study compared physician-performed ultrasound and tomosynthesis results for 3,231 asymptomatic women aged 44 to 71 years, whose median age was 51 years (J Clin Oncol. 2016 Mar 9. doi: 10.1200/JCO.2015.63.4147).
In all, the researchers detected 24 additional breast cancers, 23 of which were invasive. Thus, ultrasound detected about 7.1 additional cancers for every 1,000 screens (95% confidence interval, 4.2-10), compared with 4.0 additional cancers per 1,000 screens for tomosynthesis (95% CI, 1.8-6.2; P = .006). Only one cancer was detected by tomosynthesis alone. The rate of false-positive recalls was similar for the two modalities – 53 cases for tomosynthesis, versus 63 for ultrasound (P = .26). Rates of false-positive recalls leading to biopsy also were similar. Needle biopsies usually sufficed in recalled cases, but two women underwent surgical biopsies, both of which revealed radial scars.
If the final results of ASTOUND confirm these interim data, “it could be argued that breast tomosynthesis has little value in a setting where adjunct ultrasound is frequently used for screening women with mammography-dense breasts,” said the researchers. But tomosynthesis may have a role as a primary screening modality in other setting, especially because tomosynthesis acquisitions that also provide reconstructed 2D mammography are now available, lessening concerns about unjustified radiation exposure, they added.
The “modest” number of cancers in the interim report led to relatively wide confidence intervals, the investigators noted. Biomarker data were not available for all cancers, and both prevalent and incident ultrasound data were compared with prevalent tomosynthesis data, which might bias false-positive recall results in favor of ultrasound, they added.
Currently, 24 American states have laws requiring that women receive some level of notification about breast density with their mammography results. Dense breast tissue can hide cancer on mammography, especially when the cancer lacks calcifications, resulting in delayed diagnosis and worse outcomes. Moreover, dense breast tissue is an independent risk factor for developing breast cancer.
Because the primary goal of screening is detection of early breast cancer, ultrasound would seem the clear choice, compared with tomosynthesis. Given comparable false-positive rates in ASTOUND, the estimated cost per cancer detected would be similar or more favorable for ultrasound than tomosynthesis. Ultrasound equipment is becoming much less expensive, requires no ionizing radiation, and it is easy to guide needle biopsy of lesions seen only on ultrasound.
Preliminary results from ASTOUND are extremely important in helping to inform personalized screening choices for women with dense breasts. Guidelines on these issues are planned, but often limit recommendations to those based on evidence from randomized trials with mortality as an end point. Our knowledge of the natural history of breast cancer and results from randomized trials of mammography should inform guidelines for supplemental screening.
Dr. Wendie A. Berg is at Magee-Womens Hospital of University of Pittsburgh Medical Center. She reported serving in a consulting or advisory role with SuperSonic Imagine. These comments were taken from her accompanying editorial (J Clin Oncol. 2016 Mar 9. doi: 10.1200/JCO.2015.65.8674).
Currently, 24 American states have laws requiring that women receive some level of notification about breast density with their mammography results. Dense breast tissue can hide cancer on mammography, especially when the cancer lacks calcifications, resulting in delayed diagnosis and worse outcomes. Moreover, dense breast tissue is an independent risk factor for developing breast cancer.
Because the primary goal of screening is detection of early breast cancer, ultrasound would seem the clear choice, compared with tomosynthesis. Given comparable false-positive rates in ASTOUND, the estimated cost per cancer detected would be similar or more favorable for ultrasound than tomosynthesis. Ultrasound equipment is becoming much less expensive, requires no ionizing radiation, and it is easy to guide needle biopsy of lesions seen only on ultrasound.
Preliminary results from ASTOUND are extremely important in helping to inform personalized screening choices for women with dense breasts. Guidelines on these issues are planned, but often limit recommendations to those based on evidence from randomized trials with mortality as an end point. Our knowledge of the natural history of breast cancer and results from randomized trials of mammography should inform guidelines for supplemental screening.
Dr. Wendie A. Berg is at Magee-Womens Hospital of University of Pittsburgh Medical Center. She reported serving in a consulting or advisory role with SuperSonic Imagine. These comments were taken from her accompanying editorial (J Clin Oncol. 2016 Mar 9. doi: 10.1200/JCO.2015.65.8674).
Currently, 24 American states have laws requiring that women receive some level of notification about breast density with their mammography results. Dense breast tissue can hide cancer on mammography, especially when the cancer lacks calcifications, resulting in delayed diagnosis and worse outcomes. Moreover, dense breast tissue is an independent risk factor for developing breast cancer.
Because the primary goal of screening is detection of early breast cancer, ultrasound would seem the clear choice, compared with tomosynthesis. Given comparable false-positive rates in ASTOUND, the estimated cost per cancer detected would be similar or more favorable for ultrasound than tomosynthesis. Ultrasound equipment is becoming much less expensive, requires no ionizing radiation, and it is easy to guide needle biopsy of lesions seen only on ultrasound.
Preliminary results from ASTOUND are extremely important in helping to inform personalized screening choices for women with dense breasts. Guidelines on these issues are planned, but often limit recommendations to those based on evidence from randomized trials with mortality as an end point. Our knowledge of the natural history of breast cancer and results from randomized trials of mammography should inform guidelines for supplemental screening.
Dr. Wendie A. Berg is at Magee-Womens Hospital of University of Pittsburgh Medical Center. She reported serving in a consulting or advisory role with SuperSonic Imagine. These comments were taken from her accompanying editorial (J Clin Oncol. 2016 Mar 9. doi: 10.1200/JCO.2015.65.8674).
Ultrasound was about 1.8 times more sensitive than tomosynthesis for the incremental detection of breast cancer in women with radiologically dense breasts and negative two-dimensional mammography screening, according to interim results from the first prospective trial to directly compare the two modalities.
“However, future application of adjunct screening should consider that tomosynthesis detected more than 50% of the additional breast cancers in these women, and could potentially be [a] primary screening modality,” wrote Dr. Alberto Tagliafico of the University of Genoa (Italy) and his associates. The study was published online March 9 in the Journal of Clinical Oncology and presented simultaneously at the European Breast Cancer Conference.
Radiologically dense breast tissue undermines the sensitivity of mammography and is itself an independent risk factor for breast cancer. Recently, many states began requiring that women be informed of their breast density and adjunct screening measures, such as ultrasound. But estimates of the sensitivity of ultrasound have ranged from about 1.9 to 4.2 cancers for every 1,000 screens, said the researchers. This variance, combined with costs and concerns about false-positive recalls, have fueled debates about the value of adjunct measures in breast cancer screening, they added. To help clarify these issues, the multicenter ASTOUND (Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts) study compared physician-performed ultrasound and tomosynthesis results for 3,231 asymptomatic women aged 44 to 71 years, whose median age was 51 years (J Clin Oncol. 2016 Mar 9. doi: 10.1200/JCO.2015.63.4147).
In all, the researchers detected 24 additional breast cancers, 23 of which were invasive. Thus, ultrasound detected about 7.1 additional cancers for every 1,000 screens (95% confidence interval, 4.2-10), compared with 4.0 additional cancers per 1,000 screens for tomosynthesis (95% CI, 1.8-6.2; P = .006). Only one cancer was detected by tomosynthesis alone. The rate of false-positive recalls was similar for the two modalities – 53 cases for tomosynthesis, versus 63 for ultrasound (P = .26). Rates of false-positive recalls leading to biopsy also were similar. Needle biopsies usually sufficed in recalled cases, but two women underwent surgical biopsies, both of which revealed radial scars.
If the final results of ASTOUND confirm these interim data, “it could be argued that breast tomosynthesis has little value in a setting where adjunct ultrasound is frequently used for screening women with mammography-dense breasts,” said the researchers. But tomosynthesis may have a role as a primary screening modality in other setting, especially because tomosynthesis acquisitions that also provide reconstructed 2D mammography are now available, lessening concerns about unjustified radiation exposure, they added.
The “modest” number of cancers in the interim report led to relatively wide confidence intervals, the investigators noted. Biomarker data were not available for all cancers, and both prevalent and incident ultrasound data were compared with prevalent tomosynthesis data, which might bias false-positive recall results in favor of ultrasound, they added.
Ultrasound was about 1.8 times more sensitive than tomosynthesis for the incremental detection of breast cancer in women with radiologically dense breasts and negative two-dimensional mammography screening, according to interim results from the first prospective trial to directly compare the two modalities.
“However, future application of adjunct screening should consider that tomosynthesis detected more than 50% of the additional breast cancers in these women, and could potentially be [a] primary screening modality,” wrote Dr. Alberto Tagliafico of the University of Genoa (Italy) and his associates. The study was published online March 9 in the Journal of Clinical Oncology and presented simultaneously at the European Breast Cancer Conference.
Radiologically dense breast tissue undermines the sensitivity of mammography and is itself an independent risk factor for breast cancer. Recently, many states began requiring that women be informed of their breast density and adjunct screening measures, such as ultrasound. But estimates of the sensitivity of ultrasound have ranged from about 1.9 to 4.2 cancers for every 1,000 screens, said the researchers. This variance, combined with costs and concerns about false-positive recalls, have fueled debates about the value of adjunct measures in breast cancer screening, they added. To help clarify these issues, the multicenter ASTOUND (Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts) study compared physician-performed ultrasound and tomosynthesis results for 3,231 asymptomatic women aged 44 to 71 years, whose median age was 51 years (J Clin Oncol. 2016 Mar 9. doi: 10.1200/JCO.2015.63.4147).
In all, the researchers detected 24 additional breast cancers, 23 of which were invasive. Thus, ultrasound detected about 7.1 additional cancers for every 1,000 screens (95% confidence interval, 4.2-10), compared with 4.0 additional cancers per 1,000 screens for tomosynthesis (95% CI, 1.8-6.2; P = .006). Only one cancer was detected by tomosynthesis alone. The rate of false-positive recalls was similar for the two modalities – 53 cases for tomosynthesis, versus 63 for ultrasound (P = .26). Rates of false-positive recalls leading to biopsy also were similar. Needle biopsies usually sufficed in recalled cases, but two women underwent surgical biopsies, both of which revealed radial scars.
If the final results of ASTOUND confirm these interim data, “it could be argued that breast tomosynthesis has little value in a setting where adjunct ultrasound is frequently used for screening women with mammography-dense breasts,” said the researchers. But tomosynthesis may have a role as a primary screening modality in other setting, especially because tomosynthesis acquisitions that also provide reconstructed 2D mammography are now available, lessening concerns about unjustified radiation exposure, they added.
The “modest” number of cancers in the interim report led to relatively wide confidence intervals, the investigators noted. Biomarker data were not available for all cancers, and both prevalent and incident ultrasound data were compared with prevalent tomosynthesis data, which might bias false-positive recall results in favor of ultrasound, they added.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Ultrasound outperformed tomosynthesis for the incremental detection of breast cancer in women with negative mammograms and radiologically dense breast tissue.
Major finding: Ultrasound detected about 7.1 additional cancers for every 1,000 screens (95% confidence interval, 4.2-10), compared with 4.0 additional cancers per 1,000 tomosynthesis screens (95% CI, 1.8-6.2; P = .006).
Data source: A multicenter, prospective trial comparing the two modalities in 3,231 women.
Disclosures: The University of Genoa sponsors the ASTOUND study. Dr. Tagliafico disclosed honoraria from Esaote-Philips, patents, royalties, or other intellectual property from Springer, and travel, accommodations, and expense support from Hologic and Technologic. Four coinvestigators reported financial relationships with several device and pharmaceutical companies. The senior author and the other seven coinvestigators had no disclosures.
A Perfect Storm: Patterns of care
Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians1, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.
Mammography
Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.2 found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.3 According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.4
Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.5
The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.
Highlighting the importance of location in breast cancer care, Gehlert et al.6 asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.
With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).7
Delays in treatment
A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.8 investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.9 also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.10 demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.
Misuse of treatment
Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.11 found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.
Underuse of treatment
In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.
The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.12
Silber et al.8 also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.
Bickell et al.13 explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.
Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.14 The study by Bickell et al.13 documented underuse of this treatment in African American patients. Partridge et al.15 conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.16 analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.17 More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.
The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,20 but that assumption becomes more nuanced when the clinical trial experience is reviewed.
Clinical trial experience
Dignam20 examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.
In contrast to Dignam’s findings20, Hershman et al.21 assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs22 speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).
In their survival analysis, Hershman et al.21 controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”21 The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,22 and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.
In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.
Other installments of this column can be found in the Related Content box.
1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.
2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.
3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.
4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.
5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.
6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.
7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.
8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.
9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.
10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.
11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.
12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.
13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62. 14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.
15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.
16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.
17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.
18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.
19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.
20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.
21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.
22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.
Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.
Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.
Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.
Published in conjunction with Susan G. Komen®.
Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians1, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.
Mammography
Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.2 found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.3 According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.4
Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.5
The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.
Highlighting the importance of location in breast cancer care, Gehlert et al.6 asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.
With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).7
Delays in treatment
A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.8 investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.9 also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.10 demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.
Misuse of treatment
Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.11 found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.
Underuse of treatment
In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.
The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.12
Silber et al.8 also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.
Bickell et al.13 explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.
Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.14 The study by Bickell et al.13 documented underuse of this treatment in African American patients. Partridge et al.15 conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.16 analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.17 More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.
The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,20 but that assumption becomes more nuanced when the clinical trial experience is reviewed.
Clinical trial experience
Dignam20 examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.
In contrast to Dignam’s findings20, Hershman et al.21 assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs22 speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).
In their survival analysis, Hershman et al.21 controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”21 The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,22 and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.
In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.
Other installments of this column can be found in the Related Content box.
1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.
2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.
3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.
4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.
5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.
6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.
7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.
8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.
9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.
10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.
11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.
12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.
13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62. 14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.
15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.
16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.
17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.
18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.
19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.
20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.
21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.
22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.
Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.
Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.
Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.
Published in conjunction with Susan G. Komen®.
Editor’s Note: This is the third installment of a five-part monthly series that will discuss the pathologic, genomic, and health system factors that contribute to the racial survival disparity in breast cancer. The series, which is adapted from an article that originally appeared in CA: A Cancer Journal for Clinicians1, a journal of the American Cancer Society, will also review exciting and innovative interventions to close the survival gap. This month’s column reviews patterns of care – the second element in the perfect storm.
Mammography
Despite advances in breast cancer imaging technology, the mainstay of breast cancer screening has remained mammography. Chu et al.2 found that African American women have less early-stage disease in every age group for each hormone receptor status, and this raises the concern that mammography screening might be inadequate in this population. Although historically, African American women used mammography less than did white women, this difference has fortunately disappeared with time.3 According to results from the 2010 National Health Interview Survey, among women who were 40 years or older, 50.6% of non-Hispanic African Americans and 51.5% of non-Hispanic whites reported having had a mammogram within the past year.4
Although mammography uptake may be similar between these groups, there are still differences both in quality and in follow-up of abnormal imaging results. A study of mammography capacity and quality in a large urban setting found that the facilities that served predominantly minority women were more likely to be public institutions (31% vs. 0%) and less likely to be academic (27% vs. 71%), less likely to have digital mammography (18% vs. 71%), and less likely to have dedicated breast imaging specialists reading the films (23% vs. 87%). The authors concluded that the mammography process was broken, with quality differences in the manner in which the centers provided care and reported results.5
The accompanying graphic illustrates the disparities seen in breast cancer mammography and care for women in underserved communities on Chicago’s South Side. As the figure demonstrates, there are fewer mammography centers on the city’s South Side, with the concentration of breast cancer imaging and treatment resources localized in the more affluent communities of central and northern Chicago. A total of 300,000 women who were eligible for screening went unscreened because of improper management of resources.
Highlighting the importance of location in breast cancer care, Gehlert et al.6 asserted that ensuring that inner-city health facilities have up-to-date, well-maintained equipment and that mammographers have access to continuing training and opportunities for consultation should help reduce breast cancer mortality in African Americans.
With respect to follow-up of abnormal imaging results, a large retrospective cohort study of 6,722 women with abnormal mammogram results seen at a New York academic medical center from January 2002 through December 2002 found longer times to diagnostic follow-up for African American versus white women. The median number of days to diagnostic follow-up was 20 for African American patients versus 14 for white patients. In addition, racial disparities remained significant after the researchers controlled for age, Breast Imaging Reporting and Data System (BI-RADS) category, insurance status, provider practice location, and median household income. More important, in women with a BI-RADS classification of 4 or 5 – signifying a lesion seen on mammography that is either suspicious for or highly suggestive of malignancy, respectively – the median number of days to follow-up among those without same-day additional imaging was 26 for African Americans and 14 for whites (P < .05).7
Delays in treatment
A cascade of delays also has been documented in breast cancer care for African American women. Silber et al.8 investigated factors associated with differences in breast cancer outcomes in a large population-based study using Surveillance, Epidemiology, and End Results (SEER)-Medicare data. The mean time from diagnosis to treatment was 29.2 days for African Americans versus 22.5 days for whites (P < .001). The authors also found that African Americans were more likely to have very-long treatment delays. At least 6% of African Americans did not initiate treatment within the first 3 months of diagnosis, whereas only 3% of whites failed to start treatment (P < .001). Gwyn et al.9 also found potentially clinically significant treatment delays more often for African American women than for white women. The time from medical consultation to the initiation of treatment was longer than 3 months for 22.4% of African American women versus 14.3% of white women. Three months was chosen as a clinically significant time period, because Richards et al.10 demonstrated that a delay ≥ to 3 months affects survival. Thus, delays in the diagnosis and treatment of African American women are factors that worsen the survival gap.
Misuse of treatment
Once treatment is initiated, African Americans often receive inappropriate therapy, studies have demonstrated. In a prospective analysis of 957 patients in 101 oncology practices, Griggs et al.11 found more frequent use of non–guideline concordant adjuvant chemotherapy regimens in African American women. In a univariate analysis, African American patients were more likely than were whites to receive a nonstandard regimen (19% vs. 11%; P = .047). Although we will discuss further in this column whether guidelines based on clinical trials are appropriate for African American patients, the study demonstrates that these women are not uniformly receiving standard-of-care treatment.
Underuse of treatment
In addition to misuse of treatment, studies also have examined undertreatment of African American patients with breast cancer. One study investigated chemotherapy administration among African American patients with stage I-III breast cancer at 10 different treatment sites. Compared with white patients, African Americans received a lower dose proportion (actual vs. expected dose) and lower relative dose intensity.
The authors found that between-group differences in biological and medical characteristics, such as tolerance of therapy, comorbidities, and leukocyte counts, did not explain these variations in treatment. In fact, despite the association between lower leukocyte counts and African American ethnicity, there was no evidence that white blood cell levels accounted for the difference in dose proportion or relative dose intensity. Significantly, the authors discovered that more African Americans had chemotherapy dose reductions in the first cycle of treatment, perhaps indicating physician assumptions regarding African American patients’ ability to tolerate chemotherapy.12
Silber et al.8 also examined differences in the administration of chemotherapy between white and African American breast cancer patients. The authors found that 3.7% of African Americans received both an anthracycline and a taxane; that figure rose to 5.0% among whites who were matched to African Americans at presentation.
Bickell et al.13 explored further racial disparity in the underuse of adjuvant breast cancer treatment. The researchers examined the medical records of 677 women treated surgically for stage I or II breast cancer. The study defined underuse as omissions of radiotherapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone receptor–negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm. Underuse of appropriate adjuvant treatment was found in 34% of African American patients versus 16% of white patients (P less than .001). There were racial disparities present in all three adjuvant therapies assessed.
Hormonal therapy has been shown effective in clinical trials for preventing breast cancer recurrence and death in women with early-stage breast cancer.14 The study by Bickell et al.13 documented underuse of this treatment in African American patients. Partridge et al.15 conducted the largest study of oral antineoplastic use outside of a clinical trial setting. Their study consisted of 2,378 primary breast cancer patients enrolled in New Jersey’s Medicaid or pharmaceutical assistance program; the main outcome was the number of days covered by filled tamoxifen prescriptions in the first year of therapy. The study found that nonwhite patients had significantly lower adherence rates than did whites. Although further investigation is needed to determine the drivers of this nonadherence in African American patients, medication cost has been proposed as a significant factor leading to underuse of these agents. Streeter et al.16 analyzed a nationally representative pharmacy claims database for oral antineoplastics and calculated abandonment rates for the initial claim. Not surprisingly, high cost sharing and low incomes were associated with a higher abandonment rate (P < .05). Despite being an important component of health equity research, treatment adherence has been identified by the Association of American Medical Colleges as a critically underrepresented area of disparities-focused health services research.17 More attention to this area is needed to understand the underuse of hormonal therapies in African American breast cancer patients.
The treatment strategies that have been shown to be delayed, underused, or misused in African American patients in the aforementioned studies have improved disease-free and overall survival in large randomized trials. Furthermore, diminished total dose and dose intensity of adjuvant chemotherapy both have been associated with lower breast cancer survival rates.18,19 These quality-of-care failures in breast cancer treatment for minority patients are thought to partially explain the survival disparity between African Americans and whites. It has been proposed that patients in both groups derive a similar benefit from systemic therapy when it is administered in accordance with their clinical and pathologic presentation,20 but that assumption becomes more nuanced when the clinical trial experience is reviewed.
Clinical trial experience
Dignam20 examined survival by race in several National Surgical Adjuvant Breast and Bowel Project trials. He found that the benefit from systemic adjuvant therapy for reductions in disease recurrence and mortality was comparable between African American and white patients. His survey of trials consistently indicated equivalent disease-free survival, but a mortality deficit for African Americans also was found consistently. Among African Americans, the excess risk of mortality was 21% for those who were lymph node–negative and 17% for those who were lymph node–positive. The excess mortality risk was thought to be attributable to greater mortality from noncancer causes among African American patients rather than a failure of African Americans to respond to breast cancer treatment.
In contrast to Dignam’s findings20, Hershman et al.21 assessed the association between race and treatment discontinuation/delay, white blood cell counts, and survival in women enrolled in the Southwest Oncology Group adjuvant breast cancer trials. The study found that African American women were significantly more likely to experience treatment discontinuation/delay than were white women (87% vs. 81%, respectively; P = .04). These delays were not accounted for by toxicities, which were experienced in similar proportions by race. African American women also were more likely to miss appointments (19% vs. 9%; P = .0002); perhaps, as Hassett and Griggs22 speculated, this finding speaks to economic barriers, including the inability to arrange alternate child care, miss work, or afford transportation to the clinic. Despite these barriers to care for African American patients, they still received the same mean relative dose intensity (87% vs. 86%).
In their survival analysis, Hershman et al.21 controlled for treatment-related factors such as dose reductions and delays, body surface area, baseline white blood cell counts, and other predictors of survival and still found that African Americans had worse disease-free and overall survival than did white women. The authors concluded that the study was “unable to demonstrate that any factor related to treatment quality or delivery contributed to racial differences in survival between the groups.”21 The study thus established two important findings related to the disparity gap. First, even in the controlled setting of a clinical trial, African American patients faced barriers to optimal treatment,22 and second, despite attempts to control for treatment quality and delivery, African American women still had worse outcomes. These findings suggest that tumor biology and genomics remain important.
In next month’s installment, we will discuss interventions aimed at closing the racial survival disparity in breast cancer. Eliminating racial disparities in cancer mortality through effective interventions has become an increasingly important imperative in federal, state, and community health care programs.
Other installments of this column can be found in the Related Content box.
1. Daly B, Olopade OI. A perfect storm: How tumor biology, genomics, and health care delivery patterns collide to create a racial survival disparity in breast cancer and proposed interventions for change. CA Cancer J Clin. 2015 May-Jun;65(3):221-38.
2. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates: Separating factors that affect diagnosis from factors that affect treatment. Cancer. 2003 Jun;97(11):2853-60.
3. DeLancey JO, Thun MJ, Jemal A, Ward EM. Recent trends in black-white disparities in cancer mortality. Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):2908-12.
4. DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin. 2013 Nov;63(3):151-66.
5. Ansell D, Grabler P, Whitman S, et al. A community effort to reduce the black/white breast cancer mortality disparity in Chicago. Cancer Causes Control. 2009 Nov;20(9):1681-8.
6. Gehlert S, Sohmer D, Sacks T, Mininger C, McClintock M, Olopade O. Targeting health disparities: a model linking upstream determinants to downstream interventions. Health Aff (Millwood). 2008 Mar-Apr;27(2):339-49.
7. Press R, Carrasquillo O, Sciacca RR, Giardina EG. Racial/ethnic disparities in time to follow-up after an abnormal mammogram. J Womens Health (Larchmt). 2008 Jul;17(6):923-30.
8. Silber JH, Rosenbaum PR, Clark AS, et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA. 2013 Jul;310(4):389-397.
9. Gwyn K, Bondy ML, Cohen DS, et al. Racial differences in diagnosis, treatment, and clinical delays in a population-based study of patients with newly diagnosed breast carcinoma. Cancer. 2004 Apr;100(8):1595-604.
10. Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999 Apr 3;353(9159):1119-26.
11. Griggs JJ, Culakova E, Sorbero ME, et al. Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol. 2007 Jun 20;25(18):2522-7.
12. Griggs JJ, Sorbero ME, Stark AT, Heininger SE, Dick AW. Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat. 2003 Sep;81(1):21-31.
13. Bickell NA, Wang JJ, Oluwole S, et al. Missed opportunities: racial disparities in adjuvant breast cancer treatment. J Clin Oncol. 2006 Mar 20;24(9):1357-62. 14. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84.
15. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003 Feb 15;21(4):602-6.
16. Streeter SB, Schwartzberg L, Husain N, Johnsrud M. Patient and plan characteristics affecting abandonment of oral oncolytic prescriptions. J Oncol Pract. 2011 Jul;7(3 Suppl):46s-51s.
17. Alberti PM KN, Sutton K, Johnson BH, Holve E. The state of health equity research: closing knowledge gaps to address inequities. ©2014 Association of American Medical Colleges. May not be reproduced or distributed without prior permission.
18. Wood WC, Budman DR, Korzun AH, et al. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9.
19. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst. 1998 Aug 19;90(16):1205-11.
20. Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J Natl Cancer Inst Monogr. 2001(30):36-43.
21. Hershman DL, Unger JM, Barlow WE, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol. 2009 May;27(13):2157-62.
22. Hassett MJ, Griggs JJ. Disparities in breast cancer adjuvant chemotherapy: moving beyond yes or no. J Clin Oncol. 2009 May 1;27(13):2120-1.
Bobby Daly, MD, MBA, is the chief fellow in the section of hematology/oncology at the University of Chicago Medicine. His clinical focus is breast and thoracic oncology, and his research focus is health services. Specifically, Dr. Daly researches disparities in oncology care delivery, oncology health care utilization, aggressive end-of-life oncology care, and oncology payment models. He received his MD and MBA from Harvard Medical School and Harvard Business School, both in Boston, and a BA in Economics and History from Stanford (Calif.) University. He was the recipient of the Dean’s Award at Harvard Medical and Business Schools.
Olufunmilayo Olopade, MD, FACP, OON, is the Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics, and director, Center for Global Health at the University of Chicago. She is adopting emerging high throughput genomic and informatics strategies to identify genetic and nongenetic risk factors for breast cancer in order to implement precision health care in diverse populations. This innovative approach has the potential to improve the quality of care and reduce costs while saving more lives.
Disclosures: Dr. Olopade serves on the Medical Advisory Board for CancerIQ. Dr. Daly serves as a director of Quadrant Holdings Corporation and receives compensation from this entity. Frontline Medical Communications is a subsidiary of Quadrant Holdings Corporation.
Published in conjunction with Susan G. Komen®.
FDA approves fulvestrant for use in combination with palbociclib
The Food and Drug Administration has expanded the indication for fulvestrant to include use in combination with palbociclib for the treatment of women with hormone receptor–positive (HR+), human epidermal growth factor receptor–2 negative (HER2–) advanced or metastatic breast cancer in women whose cancer has progressed after endocrine therapy.
The FDA first approved fulvestrant in 2002 as a monotherapy for the treatment of postmenopausal women with HR+ metastatic breast cancer that had progressed following endocrine therapy.
Expanded approval is based on data from the Phase III PALOMA-3 trial that found a 4.9 month improvement in progression-free survival with the combination of fulvestrant 500 mg and palbociclib 125 mg, compared with fulvestrant and placebo, in women with HR+ HER2– advanced breast cancer whose disease had progressed after endocrine therapy. Improvement in progression-free survival was seen irrespective of menopausal status, according to a press release from AstraZeneca, makers of fulvestrant.
The most common adverse reactions of any grade reported in PALOMA-3 of the combination vs. fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%), according to the press release.
Fulvestrant is marketed as Faslodex. The new label with prescribing information can be found on the FDA website.
The Food and Drug Administration has expanded the indication for fulvestrant to include use in combination with palbociclib for the treatment of women with hormone receptor–positive (HR+), human epidermal growth factor receptor–2 negative (HER2–) advanced or metastatic breast cancer in women whose cancer has progressed after endocrine therapy.
The FDA first approved fulvestrant in 2002 as a monotherapy for the treatment of postmenopausal women with HR+ metastatic breast cancer that had progressed following endocrine therapy.
Expanded approval is based on data from the Phase III PALOMA-3 trial that found a 4.9 month improvement in progression-free survival with the combination of fulvestrant 500 mg and palbociclib 125 mg, compared with fulvestrant and placebo, in women with HR+ HER2– advanced breast cancer whose disease had progressed after endocrine therapy. Improvement in progression-free survival was seen irrespective of menopausal status, according to a press release from AstraZeneca, makers of fulvestrant.
The most common adverse reactions of any grade reported in PALOMA-3 of the combination vs. fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%), according to the press release.
Fulvestrant is marketed as Faslodex. The new label with prescribing information can be found on the FDA website.
The Food and Drug Administration has expanded the indication for fulvestrant to include use in combination with palbociclib for the treatment of women with hormone receptor–positive (HR+), human epidermal growth factor receptor–2 negative (HER2–) advanced or metastatic breast cancer in women whose cancer has progressed after endocrine therapy.
The FDA first approved fulvestrant in 2002 as a monotherapy for the treatment of postmenopausal women with HR+ metastatic breast cancer that had progressed following endocrine therapy.
Expanded approval is based on data from the Phase III PALOMA-3 trial that found a 4.9 month improvement in progression-free survival with the combination of fulvestrant 500 mg and palbociclib 125 mg, compared with fulvestrant and placebo, in women with HR+ HER2– advanced breast cancer whose disease had progressed after endocrine therapy. Improvement in progression-free survival was seen irrespective of menopausal status, according to a press release from AstraZeneca, makers of fulvestrant.
The most common adverse reactions of any grade reported in PALOMA-3 of the combination vs. fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%), according to the press release.
Fulvestrant is marketed as Faslodex. The new label with prescribing information can be found on the FDA website.
Daily updates from the Miami Breast Cancer Conference begin March 11
Unable to attend the Miami Breast Cancer Conference? No problem. Oncology Practice will be sending out daily e-mail updates from the conference with summaries of the presentations and video interviews with thought leaders in attendance. Conference presentations will not only cover novel treatment approaches, but also will outline the specifics for applying state-of-the-art treatment strategies to care for patients with breast cancer. Several controversies in the field also will be discussed.
Highly anticipated sessions include: a point/counterpoint on BCT vs. Mastectomy: Is It Time to Stop Giving Patients a Choice?; The Pros and Cons of Contralateral Risk-Reducing Mastectomy; An Immunotherapy Update on Vaccines; and New Developments in Adjuvant Endocrine Therapy in Premenopausal Patients.
View the complete program here and look for multimedia conference coverage to arrive in your e-mail inbox beginning March 11.
Unable to attend the Miami Breast Cancer Conference? No problem. Oncology Practice will be sending out daily e-mail updates from the conference with summaries of the presentations and video interviews with thought leaders in attendance. Conference presentations will not only cover novel treatment approaches, but also will outline the specifics for applying state-of-the-art treatment strategies to care for patients with breast cancer. Several controversies in the field also will be discussed.
Highly anticipated sessions include: a point/counterpoint on BCT vs. Mastectomy: Is It Time to Stop Giving Patients a Choice?; The Pros and Cons of Contralateral Risk-Reducing Mastectomy; An Immunotherapy Update on Vaccines; and New Developments in Adjuvant Endocrine Therapy in Premenopausal Patients.
View the complete program here and look for multimedia conference coverage to arrive in your e-mail inbox beginning March 11.
Unable to attend the Miami Breast Cancer Conference? No problem. Oncology Practice will be sending out daily e-mail updates from the conference with summaries of the presentations and video interviews with thought leaders in attendance. Conference presentations will not only cover novel treatment approaches, but also will outline the specifics for applying state-of-the-art treatment strategies to care for patients with breast cancer. Several controversies in the field also will be discussed.
Highly anticipated sessions include: a point/counterpoint on BCT vs. Mastectomy: Is It Time to Stop Giving Patients a Choice?; The Pros and Cons of Contralateral Risk-Reducing Mastectomy; An Immunotherapy Update on Vaccines; and New Developments in Adjuvant Endocrine Therapy in Premenopausal Patients.
View the complete program here and look for multimedia conference coverage to arrive in your e-mail inbox beginning March 11.
Is BRCA testing causing women to undergo unnecessary prophylactic mastectomy?
Because the prevalence of BRCA1 and BRCA2 mutations is elevated among young women diagnosed with breast cancer, guidelines recommend carrier testing for women diagnosed with this disease at age 50 years or younger.1 Are women being tested, however, and what are their treatment decisions surrounding those test results? The Young Women’s Breast Cancer Study (YWBCS) seeks to answer such questions.
Details of the study
Study investigators recruited women diagnosed with breast cancer at age 40 or younger from 11 academic and community hospitals in the United States and Canada beginning in 2006. There were 897 evaluable participants who were recruited between 2006 and 2014. Their mean age at diagnosis was 35.5 years and 86.1% of them were white non-Hispanic. A respective 84.5% and 99.8% of women had at least a college education and were insured.
Overall, BRCA testing was performed within 1 year of breast cancer diagnosis in 87% of participants, with rates rising from 77% in 2006 to 95% in 2013. Among participants tested, 7.6% had a BRCA1 mutation, 4.5% had a BRCA2 mutation, 4.6% had an indeterminate result of unknown clinical significance, and 81.3% had a negative test result.
A total of 86.4% of women found to be mutation carriers proceeded with risk-reducing bilateral mastectomy; 51.2% found not to be mutation carriers had this same prophylactic surgery.
What this evidence means for practice
Although it is encouraging to see that the proportion of young women with breast cancer who are receiving counseling and genetic testing is rising, the findings from this study of highly educated, largely white and affluent women is not generalizable to all US women diagnosed with breast cancer at a young age.
That more than half of BRCA-negative women in this study chose bilateral prophylactic mastectomy, a procedure not recommended in this population, is concerning, and reflects nationwide trends.2 The increasing use of next-generation sequencing (which yields information on moderate- and low-penetrance genes in addition to BRCA status) means that women and their providers increasingly are being confronted with genetic testing results that call for formal genetics expertise. Unfortunately, genetics counselors remain in short supply and many clinicians without specific genetics training are offering these tests. As editorialists appropriately point out, these trends may further increase the number of relatively low-risk women proceeding with unwarranted bilateral mastectomy.3 In my practice, I continue to refer women whose family or personal histories indicate high-risk status to a cancer genetics counselor for formal counseling and possible testing.
—Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- U.S. Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Clinical Summary of USPSTF Recommendation. AHRQ Publication No. 12-05164-EF-3. http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestsumm.htm. Published December 2013. Accessed February 25, 2016.
- Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27(9):1362–1367.
- Blazer KR, Slavin T, Weitzel JN. Increased reach of genetic cancer risk assessment as a tool for precision management of hereditary breast cancer [published online ahead of print February 11, 2016]. JAMA Oncol. doi:10.1001/jamaoncol.2015.5975.
Because the prevalence of BRCA1 and BRCA2 mutations is elevated among young women diagnosed with breast cancer, guidelines recommend carrier testing for women diagnosed with this disease at age 50 years or younger.1 Are women being tested, however, and what are their treatment decisions surrounding those test results? The Young Women’s Breast Cancer Study (YWBCS) seeks to answer such questions.
Details of the study
Study investigators recruited women diagnosed with breast cancer at age 40 or younger from 11 academic and community hospitals in the United States and Canada beginning in 2006. There were 897 evaluable participants who were recruited between 2006 and 2014. Their mean age at diagnosis was 35.5 years and 86.1% of them were white non-Hispanic. A respective 84.5% and 99.8% of women had at least a college education and were insured.
Overall, BRCA testing was performed within 1 year of breast cancer diagnosis in 87% of participants, with rates rising from 77% in 2006 to 95% in 2013. Among participants tested, 7.6% had a BRCA1 mutation, 4.5% had a BRCA2 mutation, 4.6% had an indeterminate result of unknown clinical significance, and 81.3% had a negative test result.
A total of 86.4% of women found to be mutation carriers proceeded with risk-reducing bilateral mastectomy; 51.2% found not to be mutation carriers had this same prophylactic surgery.
What this evidence means for practice
Although it is encouraging to see that the proportion of young women with breast cancer who are receiving counseling and genetic testing is rising, the findings from this study of highly educated, largely white and affluent women is not generalizable to all US women diagnosed with breast cancer at a young age.
That more than half of BRCA-negative women in this study chose bilateral prophylactic mastectomy, a procedure not recommended in this population, is concerning, and reflects nationwide trends.2 The increasing use of next-generation sequencing (which yields information on moderate- and low-penetrance genes in addition to BRCA status) means that women and their providers increasingly are being confronted with genetic testing results that call for formal genetics expertise. Unfortunately, genetics counselors remain in short supply and many clinicians without specific genetics training are offering these tests. As editorialists appropriately point out, these trends may further increase the number of relatively low-risk women proceeding with unwarranted bilateral mastectomy.3 In my practice, I continue to refer women whose family or personal histories indicate high-risk status to a cancer genetics counselor for formal counseling and possible testing.
—Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
Because the prevalence of BRCA1 and BRCA2 mutations is elevated among young women diagnosed with breast cancer, guidelines recommend carrier testing for women diagnosed with this disease at age 50 years or younger.1 Are women being tested, however, and what are their treatment decisions surrounding those test results? The Young Women’s Breast Cancer Study (YWBCS) seeks to answer such questions.
Details of the study
Study investigators recruited women diagnosed with breast cancer at age 40 or younger from 11 academic and community hospitals in the United States and Canada beginning in 2006. There were 897 evaluable participants who were recruited between 2006 and 2014. Their mean age at diagnosis was 35.5 years and 86.1% of them were white non-Hispanic. A respective 84.5% and 99.8% of women had at least a college education and were insured.
Overall, BRCA testing was performed within 1 year of breast cancer diagnosis in 87% of participants, with rates rising from 77% in 2006 to 95% in 2013. Among participants tested, 7.6% had a BRCA1 mutation, 4.5% had a BRCA2 mutation, 4.6% had an indeterminate result of unknown clinical significance, and 81.3% had a negative test result.
A total of 86.4% of women found to be mutation carriers proceeded with risk-reducing bilateral mastectomy; 51.2% found not to be mutation carriers had this same prophylactic surgery.
What this evidence means for practice
Although it is encouraging to see that the proportion of young women with breast cancer who are receiving counseling and genetic testing is rising, the findings from this study of highly educated, largely white and affluent women is not generalizable to all US women diagnosed with breast cancer at a young age.
That more than half of BRCA-negative women in this study chose bilateral prophylactic mastectomy, a procedure not recommended in this population, is concerning, and reflects nationwide trends.2 The increasing use of next-generation sequencing (which yields information on moderate- and low-penetrance genes in addition to BRCA status) means that women and their providers increasingly are being confronted with genetic testing results that call for formal genetics expertise. Unfortunately, genetics counselors remain in short supply and many clinicians without specific genetics training are offering these tests. As editorialists appropriately point out, these trends may further increase the number of relatively low-risk women proceeding with unwarranted bilateral mastectomy.3 In my practice, I continue to refer women whose family or personal histories indicate high-risk status to a cancer genetics counselor for formal counseling and possible testing.
—Andrew M. Kaunitz, MD
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- U.S. Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Clinical Summary of USPSTF Recommendation. AHRQ Publication No. 12-05164-EF-3. http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestsumm.htm. Published December 2013. Accessed February 25, 2016.
- Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27(9):1362–1367.
- Blazer KR, Slavin T, Weitzel JN. Increased reach of genetic cancer risk assessment as a tool for precision management of hereditary breast cancer [published online ahead of print February 11, 2016]. JAMA Oncol. doi:10.1001/jamaoncol.2015.5975.
- U.S. Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Clinical Summary of USPSTF Recommendation. AHRQ Publication No. 12-05164-EF-3. http://www.uspreventiveservicestaskforce.org/uspstf12/brcatest/brcatestsumm.htm. Published December 2013. Accessed February 25, 2016.
- Tuttle TM, Jarosek S, Habermann EB, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27(9):1362–1367.
- Blazer KR, Slavin T, Weitzel JN. Increased reach of genetic cancer risk assessment as a tool for precision management of hereditary breast cancer [published online ahead of print February 11, 2016]. JAMA Oncol. doi:10.1001/jamaoncol.2015.5975.
Prospective study confirms chemo not needed after low Recurrence Score
Patients with hormone receptor-positive breast cancer at high risk for recurrence by traditional parameters, but with a low 21-gene Recurrence Score (RS) can safely avoid chemotherapy, according to results of the phase III PlanB trial.
In this prospective trial, patients with intermediate to high risk breast cancer receiving adjuvant chemotherapy based on RS and those receiving no adjuvant chemotherapy based on RS of 11 or less had similar 3-year disease-free survival (DFS) rates.
In patients with pN0 to 1 breast cancer, 3-year DFS was 98.4% (95% CI, 97.0% to 99.8%) for patients with RS of 11 or less (no adjuvant chemotherapy); 97.5% (95% CI, 95.9% to 99.0%) for RS of 12 to 25 (with adjuvant chemotherapy); and 94.9% (95% CI, 91.4% to 98.4%) for RS greater than 25 (with adjuvant chemotherapy) (P = .05 for RS greater than 25 vs. others).
“The most important finding in our study is the high 3-year DFS (98%) in patients with low RS (11 or less) and no chemotherapy, despite being high risk by traditional parameters. Even with an only 3-year follow-up, such a high rate of DFS almost excludes possible benefit from adjuvant chemotherapy,” wrote Dr. Oleg Gluz of the West German Study Group, Breast Center Niederrhein, Evangelical Hospital Bethesda, Germany, and colleagues (J Clin Oncol 2016 Feb 29. doi: 10.1200/JCO.2015.63.5383).
Univariate analysis showed RS to be a prognostic factor for DFS, along with nodal status, grade, concentration of the Ki-67 protein encoded by the MKI67 gene, estrogen and progesterone receptor status, and tumor size. In multivariate analysis, fractionally ranked RS was associated with DFS (hazard ratio [HR], 1.68; 95% CI, 1.04 to 2.74; P = .035), as were node status (pN1-3 vs. pN0: HR, 2.45; 95% CI, 1.39 to 4.29, P = .001) and centrally-determined grade (G3 vs. G1 and G2: HR, 2.27; 95% CI, 1.28 to 4.02; P = .005).
The study demonstrated substantial disagreement in grade assessment by central vs. local pathology reviews, with 44% discordance in locally HR-positive tumors. Investigators suggest that use of RS may help to make treatment decisions more homogeneous and reliable, regardless of where patients are treated.
The results suggest that patients N0 to N1 breast cancer with low RS scores derive little benefit from adjuvant chemotherapy, but benefits for patients with intermediate RS scores (12 to 25) are unclear. Prospective trials are underway to address this question.
The prospective, randomized PlanB trial recruited 3,198 patients from 93 German centers from 2009 to 2011. RS scores were available for 2,568 patients with HR-positive, HER2-negative, intermediate to high risk breast cancer. In total, 18.1% had RS of 11 or less, 60.4% had RS from 12 to 25, and 21.6% had RS greater than 25.
Research was supported by Genomic Health, Sanofi Aventis, and Amgen. Dr. Gluz reported consulting or advisory roles with Genomic Health and NanoString Technologies. Several of his coauthors reported ties to industry sources.
Patients with hormone receptor-positive breast cancer at high risk for recurrence by traditional parameters, but with a low 21-gene Recurrence Score (RS) can safely avoid chemotherapy, according to results of the phase III PlanB trial.
In this prospective trial, patients with intermediate to high risk breast cancer receiving adjuvant chemotherapy based on RS and those receiving no adjuvant chemotherapy based on RS of 11 or less had similar 3-year disease-free survival (DFS) rates.
In patients with pN0 to 1 breast cancer, 3-year DFS was 98.4% (95% CI, 97.0% to 99.8%) for patients with RS of 11 or less (no adjuvant chemotherapy); 97.5% (95% CI, 95.9% to 99.0%) for RS of 12 to 25 (with adjuvant chemotherapy); and 94.9% (95% CI, 91.4% to 98.4%) for RS greater than 25 (with adjuvant chemotherapy) (P = .05 for RS greater than 25 vs. others).
“The most important finding in our study is the high 3-year DFS (98%) in patients with low RS (11 or less) and no chemotherapy, despite being high risk by traditional parameters. Even with an only 3-year follow-up, such a high rate of DFS almost excludes possible benefit from adjuvant chemotherapy,” wrote Dr. Oleg Gluz of the West German Study Group, Breast Center Niederrhein, Evangelical Hospital Bethesda, Germany, and colleagues (J Clin Oncol 2016 Feb 29. doi: 10.1200/JCO.2015.63.5383).
Univariate analysis showed RS to be a prognostic factor for DFS, along with nodal status, grade, concentration of the Ki-67 protein encoded by the MKI67 gene, estrogen and progesterone receptor status, and tumor size. In multivariate analysis, fractionally ranked RS was associated with DFS (hazard ratio [HR], 1.68; 95% CI, 1.04 to 2.74; P = .035), as were node status (pN1-3 vs. pN0: HR, 2.45; 95% CI, 1.39 to 4.29, P = .001) and centrally-determined grade (G3 vs. G1 and G2: HR, 2.27; 95% CI, 1.28 to 4.02; P = .005).
The study demonstrated substantial disagreement in grade assessment by central vs. local pathology reviews, with 44% discordance in locally HR-positive tumors. Investigators suggest that use of RS may help to make treatment decisions more homogeneous and reliable, regardless of where patients are treated.
The results suggest that patients N0 to N1 breast cancer with low RS scores derive little benefit from adjuvant chemotherapy, but benefits for patients with intermediate RS scores (12 to 25) are unclear. Prospective trials are underway to address this question.
The prospective, randomized PlanB trial recruited 3,198 patients from 93 German centers from 2009 to 2011. RS scores were available for 2,568 patients with HR-positive, HER2-negative, intermediate to high risk breast cancer. In total, 18.1% had RS of 11 or less, 60.4% had RS from 12 to 25, and 21.6% had RS greater than 25.
Research was supported by Genomic Health, Sanofi Aventis, and Amgen. Dr. Gluz reported consulting or advisory roles with Genomic Health and NanoString Technologies. Several of his coauthors reported ties to industry sources.
Patients with hormone receptor-positive breast cancer at high risk for recurrence by traditional parameters, but with a low 21-gene Recurrence Score (RS) can safely avoid chemotherapy, according to results of the phase III PlanB trial.
In this prospective trial, patients with intermediate to high risk breast cancer receiving adjuvant chemotherapy based on RS and those receiving no adjuvant chemotherapy based on RS of 11 or less had similar 3-year disease-free survival (DFS) rates.
In patients with pN0 to 1 breast cancer, 3-year DFS was 98.4% (95% CI, 97.0% to 99.8%) for patients with RS of 11 or less (no adjuvant chemotherapy); 97.5% (95% CI, 95.9% to 99.0%) for RS of 12 to 25 (with adjuvant chemotherapy); and 94.9% (95% CI, 91.4% to 98.4%) for RS greater than 25 (with adjuvant chemotherapy) (P = .05 for RS greater than 25 vs. others).
“The most important finding in our study is the high 3-year DFS (98%) in patients with low RS (11 or less) and no chemotherapy, despite being high risk by traditional parameters. Even with an only 3-year follow-up, such a high rate of DFS almost excludes possible benefit from adjuvant chemotherapy,” wrote Dr. Oleg Gluz of the West German Study Group, Breast Center Niederrhein, Evangelical Hospital Bethesda, Germany, and colleagues (J Clin Oncol 2016 Feb 29. doi: 10.1200/JCO.2015.63.5383).
Univariate analysis showed RS to be a prognostic factor for DFS, along with nodal status, grade, concentration of the Ki-67 protein encoded by the MKI67 gene, estrogen and progesterone receptor status, and tumor size. In multivariate analysis, fractionally ranked RS was associated with DFS (hazard ratio [HR], 1.68; 95% CI, 1.04 to 2.74; P = .035), as were node status (pN1-3 vs. pN0: HR, 2.45; 95% CI, 1.39 to 4.29, P = .001) and centrally-determined grade (G3 vs. G1 and G2: HR, 2.27; 95% CI, 1.28 to 4.02; P = .005).
The study demonstrated substantial disagreement in grade assessment by central vs. local pathology reviews, with 44% discordance in locally HR-positive tumors. Investigators suggest that use of RS may help to make treatment decisions more homogeneous and reliable, regardless of where patients are treated.
The results suggest that patients N0 to N1 breast cancer with low RS scores derive little benefit from adjuvant chemotherapy, but benefits for patients with intermediate RS scores (12 to 25) are unclear. Prospective trials are underway to address this question.
The prospective, randomized PlanB trial recruited 3,198 patients from 93 German centers from 2009 to 2011. RS scores were available for 2,568 patients with HR-positive, HER2-negative, intermediate to high risk breast cancer. In total, 18.1% had RS of 11 or less, 60.4% had RS from 12 to 25, and 21.6% had RS greater than 25.
Research was supported by Genomic Health, Sanofi Aventis, and Amgen. Dr. Gluz reported consulting or advisory roles with Genomic Health and NanoString Technologies. Several of his coauthors reported ties to industry sources.
Key clinical point: Patients with hormone-receptor–positive (HR-positive) breast cancer at high risk for recurrence by traditional parameters, but with 21-gene Recurrence Score (RS) of 11 or less, did not receive adjuvant chemotherapy and had excellent 3-year survival.
Major finding: In patients with pN0 to 1 breast cancer, 3-year disease-free survival (DFS) was 98.4% (95% CI, 97.0% to 99.8%) for patients with RS of 11 or less (no adjuvant chemotherapy); 97.5% (95% CI, 95.9% to 99.0%) for RS of 12 to 25 (with adjuvant chemotherapy); and 94.9% (95% CI, 91.4% to 98.4%) for RS greater than 25 (with adjuvant chemotherapy) (P = .05 for RS greater than 25 vs. others).
Data source: The prospective, randomized PlanB trial included 2,568 HR-positive, HER2-negative patients with intermediate to high risk breast cancer.
Disclosures: Research was supported by Genomic Health, Sanofi Aventis, and Amgen. Dr. Gluz reported consulting or advisory roles with Genomic Health and NanoString Technologies. Several of his coauthors reported ties to industry sources.
Prevention driving increase in mastectomies
The overall mastectomy rate rose 36% from 2005 to 2013, even though “the incidence of breast cancer overall remained stable,” according to the Agency for Healthcare Research and Quality (AHRQ).
The rate of bilateral mastectomies jumped 226% over that time period, going from 9.1 per 100,000 adult women in 2005 to 29.7 per 100,000 in 2013. The unilateral mastectomy rate, starting at 57.3 per 100,000 women in 2005, rose to 69.8 in 2009 and then fell to 60.6 in 2013, for an increase of 6% overall, the AHRQ reported.
The rate of bilateral mastectomies without any cancer diagnosis increased from 2.0 to 4.4 per 100,000 from 2005 to 2013, and the unilateral rate rose from 2.7 to 3.7 per 100,000, the report noted.
Both unilateral and bilateral mastectomies are increasingly performed as outpatient procedures. The rate done in hospital-based ambulatory surgery settings nearly doubled from 16.1 to 31 per 100,000 women, and the overall proportion performed in ambulatory settings reached 45% in 2013, the AHRQ said.
The analysis shows that “more women are opting for mastectomies, particularly preventive double mastectomies, and more of those surgeries are being done as outpatient procedures,” AHRQ Director Rick Kronick, Ph.D., said in a written statement. These “changing patterns of care for breast cancer [highlight] the need for further evidence about the effects of choices women are making on their health, well-being, and safety.”
The analysis of the State Inpatient Databases and the State Ambulatory Surgery and Services Databases involved data from 13 states that had cases in both databases and used coding that allowed identification of unilateral versus bilateral mastectomies. Those 13 states represent more than 25% of the U.S. population.
The overall mastectomy rate rose 36% from 2005 to 2013, even though “the incidence of breast cancer overall remained stable,” according to the Agency for Healthcare Research and Quality (AHRQ).
The rate of bilateral mastectomies jumped 226% over that time period, going from 9.1 per 100,000 adult women in 2005 to 29.7 per 100,000 in 2013. The unilateral mastectomy rate, starting at 57.3 per 100,000 women in 2005, rose to 69.8 in 2009 and then fell to 60.6 in 2013, for an increase of 6% overall, the AHRQ reported.
The rate of bilateral mastectomies without any cancer diagnosis increased from 2.0 to 4.4 per 100,000 from 2005 to 2013, and the unilateral rate rose from 2.7 to 3.7 per 100,000, the report noted.
Both unilateral and bilateral mastectomies are increasingly performed as outpatient procedures. The rate done in hospital-based ambulatory surgery settings nearly doubled from 16.1 to 31 per 100,000 women, and the overall proportion performed in ambulatory settings reached 45% in 2013, the AHRQ said.
The analysis shows that “more women are opting for mastectomies, particularly preventive double mastectomies, and more of those surgeries are being done as outpatient procedures,” AHRQ Director Rick Kronick, Ph.D., said in a written statement. These “changing patterns of care for breast cancer [highlight] the need for further evidence about the effects of choices women are making on their health, well-being, and safety.”
The analysis of the State Inpatient Databases and the State Ambulatory Surgery and Services Databases involved data from 13 states that had cases in both databases and used coding that allowed identification of unilateral versus bilateral mastectomies. Those 13 states represent more than 25% of the U.S. population.
The overall mastectomy rate rose 36% from 2005 to 2013, even though “the incidence of breast cancer overall remained stable,” according to the Agency for Healthcare Research and Quality (AHRQ).
The rate of bilateral mastectomies jumped 226% over that time period, going from 9.1 per 100,000 adult women in 2005 to 29.7 per 100,000 in 2013. The unilateral mastectomy rate, starting at 57.3 per 100,000 women in 2005, rose to 69.8 in 2009 and then fell to 60.6 in 2013, for an increase of 6% overall, the AHRQ reported.
The rate of bilateral mastectomies without any cancer diagnosis increased from 2.0 to 4.4 per 100,000 from 2005 to 2013, and the unilateral rate rose from 2.7 to 3.7 per 100,000, the report noted.
Both unilateral and bilateral mastectomies are increasingly performed as outpatient procedures. The rate done in hospital-based ambulatory surgery settings nearly doubled from 16.1 to 31 per 100,000 women, and the overall proportion performed in ambulatory settings reached 45% in 2013, the AHRQ said.
The analysis shows that “more women are opting for mastectomies, particularly preventive double mastectomies, and more of those surgeries are being done as outpatient procedures,” AHRQ Director Rick Kronick, Ph.D., said in a written statement. These “changing patterns of care for breast cancer [highlight] the need for further evidence about the effects of choices women are making on their health, well-being, and safety.”
The analysis of the State Inpatient Databases and the State Ambulatory Surgery and Services Databases involved data from 13 states that had cases in both databases and used coding that allowed identification of unilateral versus bilateral mastectomies. Those 13 states represent more than 25% of the U.S. population.
