January 13, 2012 — There has been a significant increase in "low-risk" and "ultra-low-risk" breast cancers among women 49 to 60 years of age in the era of population-wide mammography screening, suggests a new study that examined molecular profiling evidence.
"Screening appears to preferentially identify the low-risk lesions in the population today," the authors conclude.
The study, published in the December issue of Breast Cancer Research and Treatment, provides the "first molecular evidence of the increased detection of very-low-risk lesions over time," say the authors, led by Laura Esserman, MD, MBA, from the University of California, San Francisco.
The study used data from the Netherlands, and compared a cohort of women diagnosed with breast cancer from 1984 to 1992 (when mammography was not routinely offered) with a cohort of women diagnosed from 2004 to 2006 (the mammography-screening era).
When women 49 to 60 years of age in the 2 cohorts were compared, there was less low-risk breast cancer in the earlier cohort (40.6%; 67 of 165) than in the later cohort (58%; 119 of 205).
The study was limited to women with node-negative breast cancer. Risk was assessed using the Netherlands Cancer Institute's 70-gene breast cancer prognosis test, now commercially known as MammaPrint (marketed by Agendia). The test, which has been proven to be predictive of overall survival and the development of distant metastases, also identifies ultra-low-risk disease.
The investigators reported on a subset of ultra-low-risk women in the 2 cohorts and, once again, found increasing numbers over time.
In the earlier cohort, 10% of women 49 to 60 years of age had ultra-low-risk breast cancer, compared with 30% of women in the same age range in the later cohort.
Notably, among women younger than 40 years, there was no significant increase in low-risk disease between the 2 time cohorts.
What do these results mean? The authors believe they should lead to changes in breast cancer screening and care. They suggest that because there has been an increase in less-aggressive breast cancer, there needs to be an associated increase in less-aggressive treatment and even, in some cases, less-aggressive diagnosis.
"The study provides information that will allow us to improve screening," write the authors. They suggest that molecular tests such as MammaPrint and Oncotype DX (marketed by Genomic Health) could be used at the time of screening "to help identify low-risk tumors." Currently, the tests are used after diagnosis to help guide treatment.
An expert not associated with the study balked at the idea of using these tests at the time of screening.
"The concept of adding molecular profiling to screening sounds very attractive," said Kandace McGuire, MD, from the division of surgical oncology at the Magee-Womens Hospital of University of Pittsburgh Medical Center in Pennsylvania. But molecular tests require biopsies, she explained, which would be inappropriate at the screening level.
"Using this technology would actually not save women biopsies. It could be used to guide treatment, but not diagnosis," she said about the 70-gene test.
Despite the fact that the authors of the paper present "a rationale for integrating molecular testing at the time of screening," the primary purpose of the 70-gene test is to avoid overtreatment, said senior author Laura van 't Veer, PhD, who is also from the University of California, San Francisco.
Criticisms aside, Dr. McGuire admires the research. "In general, I think this is a thought-provoking paper. It does suggest that most of the screening-detected tumors are indolent and may have never amounted to clinically significant cancers in postmenopausal women," she said.
Avoiding Biopsies
Dr. Esserman and coauthors believe that their finding that many breast cancers are slow- to moderate-growth tumors "should enable us to reset thresholds for biopsy for very-low-risk mammographic lesions." The authors are referring to BI-RADS (Breast Imaging Reporting and Data System) 4A lesions, which are by definition suspicious but "almost always turn out to be benign," they say.
Dr. McGuire is not comfortable with any proposed change in management without evidence.
Both the study authors and Dr. McGuire agree that further study is needed to see how clinicians can modify the screening and management of low-risk cancers and lesions.
Also, Dr. McGuire said that the development of biomarkers that allow biopsies to be avoided would be a huge boon to women.
"Many centers, including Pittsburgh, are actually looking for circulating serum markers that may act as a surrogate for these molecular profiles, so that a biopsy is not required for risk stratification, and might actually lead to a change in diagnosis and biopsy rates," she said.
Good News for Aging Women
The MammaPrint 70-gene test was developed to predict long-term outcome in the absence of systemic therapy on a consecutive series of breast cancer patients from the Netherlands Cancer Institute. The test divides scores into 2 categories: good (low risk) and poor (high risk) prognosis.
The test was validated in a cohort of patients from 5 European centers in the TRANSBIG study. Over a median follow-up period of 13.6 years, a poor-prognosis signature was associated with a hazard ratio (HR) of 2.32 (95% confidence interval [CI], 1.35 to 4.00) for time to distant metastasis and a HR of 2.79 (95% CI, 1.60 to 4.87) for overall survival.
In this study, 866 patients were analyzed in the 2 cohorts and were divided into groups by age (younger than 40 years, 40 to 48 years, 49 to 60 years, and older than 60 years). Regardless of the cohort, a good prognosis with the 70-gene test significantly increased as age increased (P < .01).
The proportion of T1, grade 1, hormone-receptor-positive tumors also significantly increased with age. In other words, there is "an increase in the likelihood of having a good-prognosis tumor as a woman ages," the authors write. This was true for the combined population and for each individual age-based and time-based cohort.
Dr. McGuire believes that molecular testing and risk stratification are especially helpful to older women making treatment decisions. In women older than 70 years with breast cancer, one study indicates that recurrence is extremely low at 12 years, with or without radiotherapy, she said (N Engl J Med. 2004;351:971-977).
"I think it would be of benefit to further stratify 'older' patients into low- and high-risk [categories], not only to tailor therapy like radiation, but also to inform us...about the benefit of various adjuvant systemic therapies. The opportunity to spare an older woman cytotoxic chemotherapy cannot be underestimated," she said.
This study is not encouraging for young women with breast cancer. More than 70% of tumors in women younger than 40 years had a poor-prognosis signature; this proportion was found in both the earlier cohort and the later cohort. In other words, the proportion has remained constant over the past 20 years, the authors point out.
This study was supported by the Early Detection Research Network, the UCSF Dean's Medical Student Summer Research Fellowship, and the Dutch Genomics Initiative Cancer Genomics Center. Senior author Laura van 't Veer, PhD, is the original creator of the 70-gene prognosis signature. Coauthor Annuska Glas is an employee of Agendia, which markets MammaPrint.
Breast Cancer Res Treat. 2011;130:725-734. Abstract
"Screening appears to preferentially identify the low-risk lesions in the population today," the authors conclude.
The study, published in the December issue of Breast Cancer Research and Treatment, provides the "first molecular evidence of the increased detection of very-low-risk lesions over time," say the authors, led by Laura Esserman, MD, MBA, from the University of California, San Francisco.
The study used data from the Netherlands, and compared a cohort of women diagnosed with breast cancer from 1984 to 1992 (when mammography was not routinely offered) with a cohort of women diagnosed from 2004 to 2006 (the mammography-screening era).
When women 49 to 60 years of age in the 2 cohorts were compared, there was less low-risk breast cancer in the earlier cohort (40.6%; 67 of 165) than in the later cohort (58%; 119 of 205).
The study was limited to women with node-negative breast cancer. Risk was assessed using the Netherlands Cancer Institute's 70-gene breast cancer prognosis test, now commercially known as MammaPrint (marketed by Agendia). The test, which has been proven to be predictive of overall survival and the development of distant metastases, also identifies ultra-low-risk disease.
The investigators reported on a subset of ultra-low-risk women in the 2 cohorts and, once again, found increasing numbers over time.
In the earlier cohort, 10% of women 49 to 60 years of age had ultra-low-risk breast cancer, compared with 30% of women in the same age range in the later cohort.
Notably, among women younger than 40 years, there was no significant increase in low-risk disease between the 2 time cohorts.
What do these results mean? The authors believe they should lead to changes in breast cancer screening and care. They suggest that because there has been an increase in less-aggressive breast cancer, there needs to be an associated increase in less-aggressive treatment and even, in some cases, less-aggressive diagnosis.
"The study provides information that will allow us to improve screening," write the authors. They suggest that molecular tests such as MammaPrint and Oncotype DX (marketed by Genomic Health) could be used at the time of screening "to help identify low-risk tumors." Currently, the tests are used after diagnosis to help guide treatment.
An expert not associated with the study balked at the idea of using these tests at the time of screening.
"The concept of adding molecular profiling to screening sounds very attractive," said Kandace McGuire, MD, from the division of surgical oncology at the Magee-Womens Hospital of University of Pittsburgh Medical Center in Pennsylvania. But molecular tests require biopsies, she explained, which would be inappropriate at the screening level.
"Using this technology would actually not save women biopsies. It could be used to guide treatment, but not diagnosis," she said about the 70-gene test.
Despite the fact that the authors of the paper present "a rationale for integrating molecular testing at the time of screening," the primary purpose of the 70-gene test is to avoid overtreatment, said senior author Laura van 't Veer, PhD, who is also from the University of California, San Francisco.
Criticisms aside, Dr. McGuire admires the research. "In general, I think this is a thought-provoking paper. It does suggest that most of the screening-detected tumors are indolent and may have never amounted to clinically significant cancers in postmenopausal women," she said.
Avoiding Biopsies
Dr. Esserman and coauthors believe that their finding that many breast cancers are slow- to moderate-growth tumors "should enable us to reset thresholds for biopsy for very-low-risk mammographic lesions." The authors are referring to BI-RADS (Breast Imaging Reporting and Data System) 4A lesions, which are by definition suspicious but "almost always turn out to be benign," they say.
Dr. McGuire is not comfortable with any proposed change in management without evidence.
Both the study authors and Dr. McGuire agree that further study is needed to see how clinicians can modify the screening and management of low-risk cancers and lesions.
Also, Dr. McGuire said that the development of biomarkers that allow biopsies to be avoided would be a huge boon to women.
"Many centers, including Pittsburgh, are actually looking for circulating serum markers that may act as a surrogate for these molecular profiles, so that a biopsy is not required for risk stratification, and might actually lead to a change in diagnosis and biopsy rates," she said.
Good News for Aging Women
The MammaPrint 70-gene test was developed to predict long-term outcome in the absence of systemic therapy on a consecutive series of breast cancer patients from the Netherlands Cancer Institute. The test divides scores into 2 categories: good (low risk) and poor (high risk) prognosis.
The test was validated in a cohort of patients from 5 European centers in the TRANSBIG study. Over a median follow-up period of 13.6 years, a poor-prognosis signature was associated with a hazard ratio (HR) of 2.32 (95% confidence interval [CI], 1.35 to 4.00) for time to distant metastasis and a HR of 2.79 (95% CI, 1.60 to 4.87) for overall survival.
In this study, 866 patients were analyzed in the 2 cohorts and were divided into groups by age (younger than 40 years, 40 to 48 years, 49 to 60 years, and older than 60 years). Regardless of the cohort, a good prognosis with the 70-gene test significantly increased as age increased (P < .01).
The proportion of T1, grade 1, hormone-receptor-positive tumors also significantly increased with age. In other words, there is "an increase in the likelihood of having a good-prognosis tumor as a woman ages," the authors write. This was true for the combined population and for each individual age-based and time-based cohort.
Dr. McGuire believes that molecular testing and risk stratification are especially helpful to older women making treatment decisions. In women older than 70 years with breast cancer, one study indicates that recurrence is extremely low at 12 years, with or without radiotherapy, she said (N Engl J Med. 2004;351:971-977).
"I think it would be of benefit to further stratify 'older' patients into low- and high-risk [categories], not only to tailor therapy like radiation, but also to inform us...about the benefit of various adjuvant systemic therapies. The opportunity to spare an older woman cytotoxic chemotherapy cannot be underestimated," she said.
This study is not encouraging for young women with breast cancer. More than 70% of tumors in women younger than 40 years had a poor-prognosis signature; this proportion was found in both the earlier cohort and the later cohort. In other words, the proportion has remained constant over the past 20 years, the authors point out.
This study was supported by the Early Detection Research Network, the UCSF Dean's Medical Student Summer Research Fellowship, and the Dutch Genomics Initiative Cancer Genomics Center. Senior author Laura van 't Veer, PhD, is the original creator of the 70-gene prognosis signature. Coauthor Annuska Glas is an employee of Agendia, which markets MammaPrint.
Breast Cancer Res Treat. 2011;130:725-734. Abstract
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