August 31, 2011 — Some older women with hormone-responsive breast cancer can forgo adjuvant endocrine and chemotherapy and not be at increased risk for mortality, according to a Danish study published online today in the Journal of the National Cancer Institute.
In the study, the investigators analyzed 3197 systemically untreated early breast cancer patients of all ages who had hormone-responsive node-negative disease and tumors of 20 mm or less.
The national guidelines of the Danish Breast Cancer Cooperative Group dictate that such patients not be treated with systemic adjuvant therapy.
The investigators found that women in this group who were 60 years or older with grade 1 tumors measuring up to 10 mm (n = 458) were not at increased risk for mortality, compared with women in this age group in the general population in Denmark (adjusted relative risk, 1.02; 95% confidence interval [CI], 0.89 to 1.16).
Thus, there was a "small subgroup" of women in the study "who experience a prognosis similar to the background population of women even without systemic adjuvant therapy," write the authors, led by Peer Christiansen, MD, from the Aarhus University Hospital in Denmark.
In an accompanying editorial, 2 American experts emphasize that such women are a minority of breast cancer patients.
The women who "do not stand to gain any survival benefit from systemic adjuvant therapy" represent a "very small fraction" of the women in the study, say Jennifer Griggs, MD, and Daniel Hayes, MD, from the University of Michigan Cancer Center in Ann Arbor. Furthermore, they are "an even smaller proportion of the overall population of women diagnosed with breast cancer," they write.
Lead author Dr. Christiansen echoed those comments: "In Denmark, 85% of all patients with breast cancer have hormone-receptor-positive tumors. The low-risk group of patients, which we identified in our study, makes up less than 10% of the total population of breast cancer patients," he told Medscape Medical News.
Challenge to Prevailing Opinion
Small numbers aside, the findings represent a challenge to prevailing opinion in breast cancer, suggest the study authors.
"The Panel at the 2009 St. Gallen International Breast Cancer Conference [in Switzerland] recommended adjuvant endocrine treatment in almost all patients whose tumors show evidence of endocrine responsiveness," they observe. "The present results indicate that there is a small subgroup of node-negative patients who might not benefit from such an approach."
At the same time, the study suggests that adjuvant systemic therapy is potentially life-saving treatment in many women with early breast cancer.
In the study, younger women and those with larger tumors had increased mortality rates.
Compared with the general population of age-matched women, the mortality rate was associated with larger tumor size (11–20 mm vs 1–10 mm; standard mortality rate [SMR], 1.42) and with age (35 to 59 years; SMR > 1).
Overall, women with breast cancer had higher mortality rates than the general population, the investigators found. In the study population, there were 970 deaths; the expected number of deaths was 737, which is an excess mortality of 233 deaths (SMR, 1.32; 95% confidence interval [CI], 1.24 to 1.40). Mortality rates were 2356 per 100,000 person-years in the study population and 1790 per 100,000 person-years in the general population of women.
The median follow-up after surgery was 14.8 years. The breast cancers were diagnosed between 1989 and 2001 and were tracked in the Danish Breast Cancer Cooperative Group database.
Not Unprecedented
Other research has found that adjuvant endocrine therapy does not reduce the risk for mortality in patients with very small node-negative hormone-receptor-positive breast cancer, observe Drs. Griggs and Dr. Hayes in their editorial. The reason for that is "because the risk of mortality is already extremely low," they note.
They cite an example of the mixed results that endocrine therapy has in women with low-risk tumors.
A study from the National Surgical Adjuvant Breast and Bowel Project (NSABP B-21) was designed to identify the role of tamoxifen and breast radiation on risk for recurrence in women with breast cancers measuring 10 mm or more in greatest dimension. "Radiation therapy and tamoxifen were effective in reducing the risk of ipsilateral recurrence, and tamoxifen was effective in reducing the risk of contralateral breast events. Tamoxifen was not associated, however, with a reduction in the risk of distant metastases," they summarize.
They note that this study and others beg the question: Whom should be treated with systemic therapy?
"The stakes in these clinical decisions are high," the editorialists say, because "omitting adjuvant therapy might allow an otherwise preventable recurrence and therefore loss of curative potential."
This study helps identify patients who might forgo systemic adjuvant treatment, say both the study authors and the editorialists. Both also say that the study is limited by the lack of immunohistochemical tumor characteristics and gene profiling.
"Data on HER2, topoisomerase (DNA) II alpha (TOP2A), and Ki67 expression would have allowed us to make a more exact evaluation of the data and to perform a more precise definition of a group of patients completely matching the current low-risk criteria," say the study authors.
Research into which patients can forgo chemotherapy, which is more toxic than endocrine therapy, has included studies that look at single-gene proliferative markers, such as Ki67 and multiparameter assays (e.g., the 21-gene recurrence score), "which can quantify the risk of distant recurrences in patients who take adjuvant tamoxifen," write Drs. Griggs and Hayes. "Such tumor attributes have the potential to identify node-negative hormone-receptor-positive patients with such a favorable prognosis that they should be treated with endocrine treatment only and simply do not require chemotherapy," they write.
The Danish study shows that some women with "very low-risk invasive cancers" are "exceedingly unlikely" to "reap a survival benefit" from either form of systemic treatment, the editorialists write. Still, they emphasize that patients and their preferences play a "critical role in decision-making" with regard to possibly forgoing endocrine therapy.
The editorial writers were supported in part by grants from the National Cancer Institute and the Fashion Footwear Charitable Foundation of New York.
J Natl Cancer Inst. Published online August 31, 2011. Abstract, Editorial
In the study, the investigators analyzed 3197 systemically untreated early breast cancer patients of all ages who had hormone-responsive node-negative disease and tumors of 20 mm or less.
The national guidelines of the Danish Breast Cancer Cooperative Group dictate that such patients not be treated with systemic adjuvant therapy.
The investigators found that women in this group who were 60 years or older with grade 1 tumors measuring up to 10 mm (n = 458) were not at increased risk for mortality, compared with women in this age group in the general population in Denmark (adjusted relative risk, 1.02; 95% confidence interval [CI], 0.89 to 1.16).
Thus, there was a "small subgroup" of women in the study "who experience a prognosis similar to the background population of women even without systemic adjuvant therapy," write the authors, led by Peer Christiansen, MD, from the Aarhus University Hospital in Denmark.
In an accompanying editorial, 2 American experts emphasize that such women are a minority of breast cancer patients.
The women who "do not stand to gain any survival benefit from systemic adjuvant therapy" represent a "very small fraction" of the women in the study, say Jennifer Griggs, MD, and Daniel Hayes, MD, from the University of Michigan Cancer Center in Ann Arbor. Furthermore, they are "an even smaller proportion of the overall population of women diagnosed with breast cancer," they write.
Lead author Dr. Christiansen echoed those comments: "In Denmark, 85% of all patients with breast cancer have hormone-receptor-positive tumors. The low-risk group of patients, which we identified in our study, makes up less than 10% of the total population of breast cancer patients," he told Medscape Medical News.
Challenge to Prevailing Opinion
Small numbers aside, the findings represent a challenge to prevailing opinion in breast cancer, suggest the study authors.
"The Panel at the 2009 St. Gallen International Breast Cancer Conference [in Switzerland] recommended adjuvant endocrine treatment in almost all patients whose tumors show evidence of endocrine responsiveness," they observe. "The present results indicate that there is a small subgroup of node-negative patients who might not benefit from such an approach."
At the same time, the study suggests that adjuvant systemic therapy is potentially life-saving treatment in many women with early breast cancer.
In the study, younger women and those with larger tumors had increased mortality rates.
Compared with the general population of age-matched women, the mortality rate was associated with larger tumor size (11–20 mm vs 1–10 mm; standard mortality rate [SMR], 1.42) and with age (35 to 59 years; SMR > 1).
Overall, women with breast cancer had higher mortality rates than the general population, the investigators found. In the study population, there were 970 deaths; the expected number of deaths was 737, which is an excess mortality of 233 deaths (SMR, 1.32; 95% confidence interval [CI], 1.24 to 1.40). Mortality rates were 2356 per 100,000 person-years in the study population and 1790 per 100,000 person-years in the general population of women.
The median follow-up after surgery was 14.8 years. The breast cancers were diagnosed between 1989 and 2001 and were tracked in the Danish Breast Cancer Cooperative Group database.
Not Unprecedented
Other research has found that adjuvant endocrine therapy does not reduce the risk for mortality in patients with very small node-negative hormone-receptor-positive breast cancer, observe Drs. Griggs and Dr. Hayes in their editorial. The reason for that is "because the risk of mortality is already extremely low," they note.
They cite an example of the mixed results that endocrine therapy has in women with low-risk tumors.
A study from the National Surgical Adjuvant Breast and Bowel Project (NSABP B-21) was designed to identify the role of tamoxifen and breast radiation on risk for recurrence in women with breast cancers measuring 10 mm or more in greatest dimension. "Radiation therapy and tamoxifen were effective in reducing the risk of ipsilateral recurrence, and tamoxifen was effective in reducing the risk of contralateral breast events. Tamoxifen was not associated, however, with a reduction in the risk of distant metastases," they summarize.
They note that this study and others beg the question: Whom should be treated with systemic therapy?
"The stakes in these clinical decisions are high," the editorialists say, because "omitting adjuvant therapy might allow an otherwise preventable recurrence and therefore loss of curative potential."
This study helps identify patients who might forgo systemic adjuvant treatment, say both the study authors and the editorialists. Both also say that the study is limited by the lack of immunohistochemical tumor characteristics and gene profiling.
"Data on HER2, topoisomerase (DNA) II alpha (TOP2A), and Ki67 expression would have allowed us to make a more exact evaluation of the data and to perform a more precise definition of a group of patients completely matching the current low-risk criteria," say the study authors.
Research into which patients can forgo chemotherapy, which is more toxic than endocrine therapy, has included studies that look at single-gene proliferative markers, such as Ki67 and multiparameter assays (e.g., the 21-gene recurrence score), "which can quantify the risk of distant recurrences in patients who take adjuvant tamoxifen," write Drs. Griggs and Hayes. "Such tumor attributes have the potential to identify node-negative hormone-receptor-positive patients with such a favorable prognosis that they should be treated with endocrine treatment only and simply do not require chemotherapy," they write.
The Danish study shows that some women with "very low-risk invasive cancers" are "exceedingly unlikely" to "reap a survival benefit" from either form of systemic treatment, the editorialists write. Still, they emphasize that patients and their preferences play a "critical role in decision-making" with regard to possibly forgoing endocrine therapy.
The editorial writers were supported in part by grants from the National Cancer Institute and the Fashion Footwear Charitable Foundation of New York.
J Natl Cancer Inst. Published online August 31, 2011. Abstract, Editorial
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