July 26, 2011 — Performing immunohistochemistry (IHC) on otherwise negative sentinel lymph nodes (SLNs) does not significantly improve survival in early breast cancer and is "not clinically warranted," according to the authors of a major study, known as Z0010, from the American College of Surgeons Oncology Group (ACSOG).
The study found that, in women with very early breast cancer and negative SLNs on standard pathologic examination, the presence of micrometastases, the tiny cancer particles that can be detected by IHC, "does not adversely affect the prognosis," explained lead author Armando Giuliano, MD, from Cedars-Sinai Medical Center in Los Angeles, California.
In other words, routinely searching for micromets in such women is not necessary because their presence does not negatively affect survival, Dr. Giuliano summarized in an interview with Medscape Medical News.
The use of IHC on SLN tissue that was already found to be negative is "very common," he said.
This IHC processing goes on in many laboratories, even though the College of American Pathologists does not recommend it in such circumstances, added Dr. Giuliano.
The use of IHC is not benign, he suggested; it might lead to "more radical treatment" than is needed.
The Z0010 study details, which are reported in the July 27 issue of JAMA, the Journal of the American Medical Association, were first presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO).
The fact that the study, which has 126 participating institutions, is an observational trial does not take away from its authority, according to the authors of an accompanying editorial.
"The report ... serves as an ideal illustration of how well-designed observational research can be conducted in surgery," write Ryan Merkow, MD, from the University of Colorado in Boulder, and Clifford Ko, MD, from the University of California, Los Angeles. The cohort study was highly standardized and designed to minimize bias and confounding, they say.
The 5210 women in the Z0010 trial had clinical T1 to T2N0M0 disease and underwent breast-conserving surgery and SLN dissection. Most also underwent systemic therapy.
The women with negative nodes on standard hematoxylin and eosin (H&E) testing (n = 3995) were then evaluated with IHC to determine if micrometastases were present but undetectable by the standard H&E pathologic technique. A total of 349 women (10.5%) were ultimately found to have positive nodes or micromets on IHC.
However, this presence of micromets in the lymph nodes did not affect survival.
At a median follow-up of 6.3 years, the patients who had micromets had a rate of survival very similar to the patients who had none. Specifically, immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7% for immunohistochemical-negative and 95.1% for immunohistochemical-positive disease; P = .64).
The Z0010 study, which enrolled patients from 1999 to 2003, is affiliated with another major clinical trial from ACSOG, Z0011. That study recommended against another common practice in early breast cancer — the use of axillary dissection in certain women who have minimal lymph node involvement. This important trial was first reported by Medscape Medical News at the 2010 ASCO meeting and, once published, became front-page news in The New York Times and other media outlets.
Bone Marrow Complexities
The story is slightly different when micrometastases are found in the bone marrow.
Many of the women in the Z0010 study underwent testing of the bone marrow (n = 3413), regardless of the status of their lymph nodes. The testing was originally optional in the study, but became mandatory. Such testing is "rarely" done in clinical practice, acknowledged Dr. Giuliano, but ACSOG wanted to know what its impact might be.
Only 3% of the tested women (n = 104) had bone marrow specimens that were positive on immunocytochemistry (ICC). The percentage is low and is in keeping with the disease stage, say the authors.
Significantly, bone marrow metastases were associated with decreased overall survival (unadjusted hazard ratio [HR] for mortality, 1.94; P = .04). The median 5-year survival rate for women with ICC-positive bone marrow was 90.1% and for women with ICC-negative bone marrow was 95%; the difference was statistically significant (P = .01).
Despite these statistically significant findings, the authors say that ICC is not routinely needed in this setting, because any spread to the bone is a rare finding in such early disease.
At the 2010 ASCO meeting, the designated discussant of the study made a point about another finding in the study that reinforces the acceptability of not doing bone marrow biopsies in these patients.
In the subset of women who were originally SLN-negative (on H&E) but who were found to have ICC-detected metastases in the bone marrow, there was not a statistically significant overall survival value (P = .16), noted William Wood, MD, from Emory University School of Medicine in Atlanta, Georgia. This is important, he said, because these are the very patients who "might not receive cytotoxic chemotherapy."
"I'm grateful that it appears to lack clinical utility," said Dr. Wood about the bone marrow findings. He said that the opposite finding would require him and other clinicians to do 33 bone marrow aspirations in SLN-negative women to find the 1 patient with bone micrometastases.
Because of current methodology, assessing occult tumor cells in the bone marrow is not efficient or feasible, add the authors. Furthermore, they found that immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% confidence interval, 0.79 to 4.26; P = .15) was not statistically significant on multivariable analysis. The variables included age, tumor type, lymphovascular invasion, estrogen-receptor status, and adjuvant systemic therapy. The only variables significantly associated with overall survival were age older than 50 years and tumor size larger than 1.0 cm, report the authors.
There might be biologic factors that are associated with a tumor micrometastasizing to the bone in the Z0010 patients, the authors say.
A previous study (Clin Cancer Res. 2006;12:5615-5621) "reported a putative stem-cell-like phenotype (CD44+CD24–/low) in immunocytochemistry-positive cells from the bone marrow of 65% of Z0010 patients," they write.
Adjuvant Therapy Common
The Z0010 trial was undertaken to resolve some conflicting study results related to micrometastatic disease in breast cancer, says Dr. Giuliano, who was at the John Wayne Cancer Institute Breast Center in Santa Monica, California, during the study period.
For example, 2 major studies have conflicting results. A long-term prospective study of occult metastases in SLNs from 790 contemporary patients with early breast cancer showed that micrometastases and isolated tumor cells did not reduce survival (J Clin Oncol. 2009;27:4679-4684). In contrast, in the 3884 patients enrolled in the National Surgical Adjuvant Breast and Bowel Project's B-32 study, occult metastases were associated with a small but statistically significant 1.2% decrease in 5-year survival (N Engl J Med. 2011;364:412-421).
At the 2010 ASCO meeting, Dr. Wood called the Z0010 study a "real-world" trial. Unlike some other trials looking at micromets in this setting, the patients in the study were treated with current clinical norms, he said. Indeed, 86.2% had either adjuvant hormonal therapy and/or adjuvant chemotherapy, report the authors.
This study was supported by National Institutes of Health and American College of Surgeons Oncology Group.
JAMA. 2011;306:385-393 and 436-437.
The study found that, in women with very early breast cancer and negative SLNs on standard pathologic examination, the presence of micrometastases, the tiny cancer particles that can be detected by IHC, "does not adversely affect the prognosis," explained lead author Armando Giuliano, MD, from Cedars-Sinai Medical Center in Los Angeles, California.
In other words, routinely searching for micromets in such women is not necessary because their presence does not negatively affect survival, Dr. Giuliano summarized in an interview with Medscape Medical News.
The use of IHC on SLN tissue that was already found to be negative is "very common," he said.
This IHC processing goes on in many laboratories, even though the College of American Pathologists does not recommend it in such circumstances, added Dr. Giuliano.
The use of IHC is not benign, he suggested; it might lead to "more radical treatment" than is needed.
The Z0010 study details, which are reported in the July 27 issue of JAMA, the Journal of the American Medical Association, were first presented at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO).
The fact that the study, which has 126 participating institutions, is an observational trial does not take away from its authority, according to the authors of an accompanying editorial.
"The report ... serves as an ideal illustration of how well-designed observational research can be conducted in surgery," write Ryan Merkow, MD, from the University of Colorado in Boulder, and Clifford Ko, MD, from the University of California, Los Angeles. The cohort study was highly standardized and designed to minimize bias and confounding, they say.
The 5210 women in the Z0010 trial had clinical T1 to T2N0M0 disease and underwent breast-conserving surgery and SLN dissection. Most also underwent systemic therapy.
The women with negative nodes on standard hematoxylin and eosin (H&E) testing (n = 3995) were then evaluated with IHC to determine if micrometastases were present but undetectable by the standard H&E pathologic technique. A total of 349 women (10.5%) were ultimately found to have positive nodes or micromets on IHC.
However, this presence of micromets in the lymph nodes did not affect survival.
At a median follow-up of 6.3 years, the patients who had micromets had a rate of survival very similar to the patients who had none. Specifically, immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7% for immunohistochemical-negative and 95.1% for immunohistochemical-positive disease; P = .64).
The Z0010 study, which enrolled patients from 1999 to 2003, is affiliated with another major clinical trial from ACSOG, Z0011. That study recommended against another common practice in early breast cancer — the use of axillary dissection in certain women who have minimal lymph node involvement. This important trial was first reported by Medscape Medical News at the 2010 ASCO meeting and, once published, became front-page news in The New York Times and other media outlets.
Bone Marrow Complexities
The story is slightly different when micrometastases are found in the bone marrow.
Many of the women in the Z0010 study underwent testing of the bone marrow (n = 3413), regardless of the status of their lymph nodes. The testing was originally optional in the study, but became mandatory. Such testing is "rarely" done in clinical practice, acknowledged Dr. Giuliano, but ACSOG wanted to know what its impact might be.
Only 3% of the tested women (n = 104) had bone marrow specimens that were positive on immunocytochemistry (ICC). The percentage is low and is in keeping with the disease stage, say the authors.
Significantly, bone marrow metastases were associated with decreased overall survival (unadjusted hazard ratio [HR] for mortality, 1.94; P = .04). The median 5-year survival rate for women with ICC-positive bone marrow was 90.1% and for women with ICC-negative bone marrow was 95%; the difference was statistically significant (P = .01).
Despite these statistically significant findings, the authors say that ICC is not routinely needed in this setting, because any spread to the bone is a rare finding in such early disease.
At the 2010 ASCO meeting, the designated discussant of the study made a point about another finding in the study that reinforces the acceptability of not doing bone marrow biopsies in these patients.
In the subset of women who were originally SLN-negative (on H&E) but who were found to have ICC-detected metastases in the bone marrow, there was not a statistically significant overall survival value (P = .16), noted William Wood, MD, from Emory University School of Medicine in Atlanta, Georgia. This is important, he said, because these are the very patients who "might not receive cytotoxic chemotherapy."
"I'm grateful that it appears to lack clinical utility," said Dr. Wood about the bone marrow findings. He said that the opposite finding would require him and other clinicians to do 33 bone marrow aspirations in SLN-negative women to find the 1 patient with bone micrometastases.
Because of current methodology, assessing occult tumor cells in the bone marrow is not efficient or feasible, add the authors. Furthermore, they found that immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% confidence interval, 0.79 to 4.26; P = .15) was not statistically significant on multivariable analysis. The variables included age, tumor type, lymphovascular invasion, estrogen-receptor status, and adjuvant systemic therapy. The only variables significantly associated with overall survival were age older than 50 years and tumor size larger than 1.0 cm, report the authors.
There might be biologic factors that are associated with a tumor micrometastasizing to the bone in the Z0010 patients, the authors say.
A previous study (Clin Cancer Res. 2006;12:5615-5621) "reported a putative stem-cell-like phenotype (CD44+CD24–/low) in immunocytochemistry-positive cells from the bone marrow of 65% of Z0010 patients," they write.
Adjuvant Therapy Common
The Z0010 trial was undertaken to resolve some conflicting study results related to micrometastatic disease in breast cancer, says Dr. Giuliano, who was at the John Wayne Cancer Institute Breast Center in Santa Monica, California, during the study period.
For example, 2 major studies have conflicting results. A long-term prospective study of occult metastases in SLNs from 790 contemporary patients with early breast cancer showed that micrometastases and isolated tumor cells did not reduce survival (J Clin Oncol. 2009;27:4679-4684). In contrast, in the 3884 patients enrolled in the National Surgical Adjuvant Breast and Bowel Project's B-32 study, occult metastases were associated with a small but statistically significant 1.2% decrease in 5-year survival (N Engl J Med. 2011;364:412-421).
At the 2010 ASCO meeting, Dr. Wood called the Z0010 study a "real-world" trial. Unlike some other trials looking at micromets in this setting, the patients in the study were treated with current clinical norms, he said. Indeed, 86.2% had either adjuvant hormonal therapy and/or adjuvant chemotherapy, report the authors.
This study was supported by National Institutes of Health and American College of Surgeons Oncology Group.
JAMA. 2011;306:385-393 and 436-437.
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