In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate eve... more In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by positron emission tomography (PET) following i.v. injection of the glucose analogue (18)F-fluorodeoxy-glucose ((18)FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To identify molecular determinants of (18)FDG retention, we interrogated the transcriptomes of human-cancer cell lines and primary tumors for metabolic pathways associated with (18)FDG radiotracer uptake. From ninety-five metabolic pathways that were interrogated, the glycolysis, and several glycolysis-related pathways (pentose phosphate, carbon fixation, aminoacyl-tRNA biosynthesis, one-carbon-pool by folate) showed the greatest transcriptional enrichment. This "FDG signature" predic...
Background Magnetic resonance imaging (MRI) can detect breast cancer in high-risk patients, but ... more Background Magnetic resonance imaging (MRI) can detect breast cancer in high-risk patients, but is associated with a significant false-positive rate resulting in unnecessary breast biopsies. More data are needed to define the role of MRI screening for specific high-risk groups. We describe our experience with MRI screening in patients with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS). Methods We retrospectively
Nature is the international weekly journal of science: a magazine style journal that publishes fu... more Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and ...
The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermi... more The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.
Background:Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node staging i... more Background:Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node staging in patients with primary operable breast cancer. An increasing proportion of these patients undergo breast-conserving surgery, and 10% to 15% will develop local relapse requiring reoperation. Although previous breast or axillary surgery is often considered a contraindication to SLN biopsy, few data support this position.
The purpose of this study is to determine the biologic impact of short-term lipophilic statin exp... more The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P < 0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.
We investigated the incidence of axillary lymph node metastases in patients with T1a (< or... more We investigated the incidence of axillary lymph node metastases in patients with T1a (< or = 0.5 cm) and T1b (> 0.5 cm and < or = 1.0 cm) breast cancers. The charts of 2000 patients who underwent axillary lymph node dissection for breast cancer at our institution from 1989 to 1991 were reviewed. Of these, 81 patients had T1a and 166 had T1b primary breast cancers. Among the 247 patients with T1a and T1b breast cancers, nodal metastases were present in 30 (12.1%), with a 7.4% positivity rate for patients with T1a and 14.5% positivity rate for T1b tumors. Of the 212 patients who had > or = 10 nodes dissected, 29 (13.7%) had positive nodes. Of those, 6 of 60 (10.0%) patients with T1a and 23 of 152 (15.1%) with T1b tumors had positive nodes. The presence of lymphovascular invasion (LVI) predicted a significantly higher nodal positivity rate (27.8% vs. 10.9%, p = 0.05). Of patients with adequately evaluated axillae, 10% with T1a and 15% with T1b cancers were found to have nodal metastases. Although LVI was significantly associated with a higher risk of lymph node metastases, we could not characterize any subgroup at acceptably low risk of nodal positivity. Until a more useful prognostic indicator is discovered, axillary dissection should continue to be part of the mainstay of management for small breast cancers.
This study examined whether the volume of isosulfan blue dye used in sentinel lymph node (SLN) ma... more This study examined whether the volume of isosulfan blue dye used in sentinel lymph node (SLN) mapping in breast cancer is related to the SLN identification rate or to the incidence of allergic reactions. From January 2001 to November 2002, 1728 breast cancer patients underwent 1832 SLN mapping procedures with the combined technique of intraparenchymal blue dye and intradermal radioisotope. Details of each procedure and all allergic reactions were prospectively recorded. Bilateral synchronous SLN procedures were considered as one dye exposure but as two distinct procedures for determining mapping success. Dye-only success was defined as the proportion of cases in which the SLN was identified by blue dye alone. Overall dye success was defined as the proportion of cases in which the SLN was identified by blue dye with or without isotope. When stratified by volume of blue dye, there were no significant differences in dye-only successes, overall dye successes, or mapping failures. Allergic reactions were documented in 31 (1.8%) of 1728 patients. Hypotensive reactions occurred in 3 (.2%) of 1728 patients; 2 (.1%) required pressor support. There was a nonsignificant trend toward fewer allergic reactions with smaller volumes of blue dye. In combined-technique SLN mapping protocols for breast cancer, using smaller volumes of blue dye may represent a means of optimizing the safety of the procedure without compromising its success.
Background The role of positron emission tomography (PET) scanning in determining the extent of ... more Background The role of positron emission tomography (PET) scanning in determining the extent of disease in patients with breast cancer has not been defined. We investigated the utility of 18F-2-fluoro-2-deoxy-D-glucose (FDG)-PET scanning compared with conventional imaging with computed tomographic scanning and bone scanning in determining the extent of disease in patients with high-risk, operable breast cancer. Methods This was a prospective study
Management of patients with breast cancers < or = 1 cm remains controversial. Reports of i... more Management of patients with breast cancers < or = 1 cm remains controversial. Reports of infrequent nodal metastases in tumors < or = 5 mm has led to suggestions that axillary dissection should be selective, and that tumor characteristics should guide adjuvant therapy. A retrospective review of 290 patients with breast cancer 1 cm in size or smaller from 1989 to 1991 was done. Distant disease-free survival (DDFS) was the primary outcome measure. There were 95 T1a (< or = 5 mm) and 196 T1b (6-10 mm) cancers. Nodal metastases were found in 8 T1a and 26 T1b tumors. Larger size, poorer differentiation, and lymphovascular invasion (LVI) were associated with more nodal metastases, but none of these trends reached statistical significance. The 6-year DDFS was 93% for node-negative and 87% for node-positive patients (P = .02). Overall, breast cancers with poorer differentiation and LVI trended toward a poorer outcome. For patients with node-negative tumors, LVI was associated with a poorer outcome (P = .03). The size of the primary tumor was not predictive of outcome. There were no nodal metastases or recurrences in the 18 patients with microinvasive breast cancer. Lymph node status is the major determinant of outcome in breast cancers 1 cm in size or smaller. Accurate axillary assessment remains crucial in management of small breast cancer.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial demonstrated that tamox... more The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial demonstrated that tamoxifen reduces the incidence of new breast cancers by 49% in women at increased risk for breast cancer development. Tamoxifen does have side effects, however, including marginally increased risks of endometrial cancer and thromboembolic events. In this study, women at increased risk for breast cancer development were offered tamoxifen. Their knowledge of tamoxifen as a chemopreventive agent was assessed, and factors influencing their acceptance of tamoxifen and willingness to take it were determined. Forty-three patients were identified who qualified to take tamoxifen for primary prevention. Patients qualified by having at least a 1.7% 5-year risk of developing breast cancer, the criteria for entry into the NSABP P-1 trial. Patients initially completed questionnaires designed to assess their knowledge of tamoxifen and its associated risks and benefits. Patients were then provided neutral educational sessions and literature delineating the actual risks and benefits of tamoxifen. Subsequently, patients' decisions regarding taking tamoxifen were reassessed. Mean patient age was 52.8 years, with a range of 39 to 74 years. Ten patients (23.2%) qualified based on the presence of lobular carcinoma in situ (LCIS), seven patients (16.3%) qualified based on increased risk secondary to age >60 years, and 26 patients (60.5%) age range 35 to 59 qualified based on risk profiles demonstrating significantly increased risk. Of the total 43 patients, two (4.7%) elected to start taking tamoxifen. Fifteen patients (34.8%) declined immediately, and 26 patients (60.5%) were undecided initially but ultimately declined. Educational sessions did not influence patients' decisions. Fear of side effects, including endometrial cancer, thromboembolic events, and menopausal symptoms, was the most commonly cited reason for declining to take tamoxifen. In this study, the vast majority of patients at increased risk for breast cancer perceived that the risks of taking tamoxifen outweighed the benefits and declined to take it.
Although many questions regarding sentinel lymph node (SLN) biopsy in breast cancer have been ans... more Although many questions regarding sentinel lymph node (SLN) biopsy in breast cancer have been answered by observational studies and, increasingly, by prospective trials, the role of intraoperative SLN assessment remains a matter of debate. Here we report in detail the results of intraoperative SLN assessment by frozen section (FS), with particular attention to variations in sensitivity and yield by histologic subtype, by tumor size, and by other clinicopathologic parameters. Five thousand two hundred ninety-eight consecutive patients with clinical stage T1-3N0 invasive breast carcinoma had SLN biopsy with intraoperative FS at Memorial Sloan Kettering Cancer Center between 1996 and 2004. We report the results of FS by sensitivity (the proportion of all positive SLN detected by FS) and by yield (the proportion of all FS procedures in which the FS was positive). The sensitivity of FS was 61% overall, was higher for invasive duct (ID) than for invasive lobular (IL) cancers (62% vs. 52%; P = 0.006), and was marginally lower for favorable subtypes (46%; P = 0.26). The yield of FS was 21% overall, with no difference between ID and IL cancers (22% vs. 21%; P = 0.49), and with a substantially lower yield for favorable subtypes (3%; P < 0.001). The yield of FS increased with tumor size for ID and IL cancers (P < 0.001), but not for favorable subtypes. For both ID and IL cancers, the sensitivity and yield of FS were significantly higher with younger patient age, increasing tumor size, and lymphovascular invasion. The yield of FS was <10% for all patients with ID or IL tumors < or =1 cm in size who were older than 60 years of age. Among all FS-positive patients, only 45% were identified by the first FS, whereas 91% were cumulatively identified by the first, second, or third FS. For patients with ID and IL cancers, the overall sensitivity of FS is >50%, but the yield of FS is <10% for individuals > or =60 years of age with T1a/b tumors. Intraoperative FS may not be worthwhile for this low-yield subset, especially for patients with invasive breast cancer of favorable type.
We sought to identify the rate of axillary recurrence after sentinel lymph node (SLN) biopsy for ... more We sought to identify the rate of axillary recurrence after sentinel lymph node (SLN) biopsy for breast cancer. SLN biopsy is a new standard of care for axillary lymph node staging in breast cancer. Nevertheless, most validated series of SLN biopsy confirm that the SLN is falsely negative in 5-10% of node-positive cases, and few studies report the rate of axillary local recurrence (LR) for that subset of patients staged by SLN biopsy alone. Through December of 2002, 4008 consecutive SLN biopsy procedures were performed at Memorial Sloan-Kettering Cancer Center for unilateral invasive breast cancer. Patients were categorized in 4 groups: SLN-negative with axillary lymph node dissection (ALND; n = 326), SLN-negative without ALND (n = 2340), SLN-positive with ALND (n = 1132), and SLN-positive without ALND (n = 210). Clinical and pathologic characteristics and follow-up data for each of the 4 cohorts were evaluated with emphasis on patterns of axillary LR. With a median follow-up of 31 months (range, 1-75), axillary LR occurred in 10/4008 (0.25%) patients overall. In 3 cases (0.07%) the axillary LR was the first site of treatment failure, in 4 (0.1%) it was coincident with breast LR, and in 3 (0.07%) it was coincident with distant metastases. Axillary LR was more frequent among the unconventionally treated SLN-positive/no ALND patients than in the other 3 conventionally treated cohorts (1.4% versus 0.18%, P = 0.013). Axillary LR after SLN biopsy, with or without ALND, is a rare event, and this low relapse rate supports wider use of SLN biopsy for breast cancer staging. There is a low-risk subset of SLN-positive patients in whom completion ALND may not be required.
In the United States, identification of the sentinel lymph node (SLN) requires the use of (99m)Tc... more In the United States, identification of the sentinel lymph node (SLN) requires the use of (99m)Tc-labeled colloid, 1% isosulfan blue dye, or both to trace the lymphatic drainage of a given neoplasm. We report our experience with adverse reactions to isosulfan blue dye during SLN mapping in breast cancer. A chart review of the breast cancer SLN database was performed; it included 2392 sequential patients who underwent SLN biopsy involving isosulfan blue dye at Memorial Sloan-Kettering Cancer Center from September 12, 1996, to August 17, 2000. Thirty-nine of 2392 patients (1.6%) had a documented allergic reaction during the mapping procedure. Most reactions (69%) produced urticaria, blue hives, a generalized rash, or pruritus. The incidence of hypotensive reactions was 0.5%. Although anaphylaxis after the injection of isosulfan blue dye is rare, this article highlights the need to suspect anaphylaxis when hemodynamic instability occurs after the injection of this compound. Our experience indicates that bronchospasm and respiratory compromise are unusual and that most patients do not require emergent intubation and can be managed with short-term pressor support. In addition, our data indicate that patients with a sulfa allergy do not display a cross-sensitivity to isosulfan blue dye. We report the largest single-institution review of adverse reactions to injection of isosulfan blue dye during sentinel lymph node mapping in breast cancer. Bronchospasm and respiratory compromise are unusual, and most patients can be treated with short-term pressor support. Patients with a sulfa allergy do not display a cross-sensitivity to isosulfan blue dye.
In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate eve... more In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by positron emission tomography (PET) following i.v. injection of the glucose analogue (18)F-fluorodeoxy-glucose ((18)FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To identify molecular determinants of (18)FDG retention, we interrogated the transcriptomes of human-cancer cell lines and primary tumors for metabolic pathways associated with (18)FDG radiotracer uptake. From ninety-five metabolic pathways that were interrogated, the glycolysis, and several glycolysis-related pathways (pentose phosphate, carbon fixation, aminoacyl-tRNA biosynthesis, one-carbon-pool by folate) showed the greatest transcriptional enrichment. This "FDG signature" predic...
Background Magnetic resonance imaging (MRI) can detect breast cancer in high-risk patients, but ... more Background Magnetic resonance imaging (MRI) can detect breast cancer in high-risk patients, but is associated with a significant false-positive rate resulting in unnecessary breast biopsies. More data are needed to define the role of MRI screening for specific high-risk groups. We describe our experience with MRI screening in patients with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS). Methods We retrospectively
Nature is the international weekly journal of science: a magazine style journal that publishes fu... more Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and ...
The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermi... more The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.
Background:Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node staging i... more Background:Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node staging in patients with primary operable breast cancer. An increasing proportion of these patients undergo breast-conserving surgery, and 10% to 15% will develop local relapse requiring reoperation. Although previous breast or axillary surgery is often considered a contraindication to SLN biopsy, few data support this position.
The purpose of this study is to determine the biologic impact of short-term lipophilic statin exp... more The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P < 0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.
We investigated the incidence of axillary lymph node metastases in patients with T1a (< or... more We investigated the incidence of axillary lymph node metastases in patients with T1a (< or = 0.5 cm) and T1b (> 0.5 cm and < or = 1.0 cm) breast cancers. The charts of 2000 patients who underwent axillary lymph node dissection for breast cancer at our institution from 1989 to 1991 were reviewed. Of these, 81 patients had T1a and 166 had T1b primary breast cancers. Among the 247 patients with T1a and T1b breast cancers, nodal metastases were present in 30 (12.1%), with a 7.4% positivity rate for patients with T1a and 14.5% positivity rate for T1b tumors. Of the 212 patients who had > or = 10 nodes dissected, 29 (13.7%) had positive nodes. Of those, 6 of 60 (10.0%) patients with T1a and 23 of 152 (15.1%) with T1b tumors had positive nodes. The presence of lymphovascular invasion (LVI) predicted a significantly higher nodal positivity rate (27.8% vs. 10.9%, p = 0.05). Of patients with adequately evaluated axillae, 10% with T1a and 15% with T1b cancers were found to have nodal metastases. Although LVI was significantly associated with a higher risk of lymph node metastases, we could not characterize any subgroup at acceptably low risk of nodal positivity. Until a more useful prognostic indicator is discovered, axillary dissection should continue to be part of the mainstay of management for small breast cancers.
This study examined whether the volume of isosulfan blue dye used in sentinel lymph node (SLN) ma... more This study examined whether the volume of isosulfan blue dye used in sentinel lymph node (SLN) mapping in breast cancer is related to the SLN identification rate or to the incidence of allergic reactions. From January 2001 to November 2002, 1728 breast cancer patients underwent 1832 SLN mapping procedures with the combined technique of intraparenchymal blue dye and intradermal radioisotope. Details of each procedure and all allergic reactions were prospectively recorded. Bilateral synchronous SLN procedures were considered as one dye exposure but as two distinct procedures for determining mapping success. Dye-only success was defined as the proportion of cases in which the SLN was identified by blue dye alone. Overall dye success was defined as the proportion of cases in which the SLN was identified by blue dye with or without isotope. When stratified by volume of blue dye, there were no significant differences in dye-only successes, overall dye successes, or mapping failures. Allergic reactions were documented in 31 (1.8%) of 1728 patients. Hypotensive reactions occurred in 3 (.2%) of 1728 patients; 2 (.1%) required pressor support. There was a nonsignificant trend toward fewer allergic reactions with smaller volumes of blue dye. In combined-technique SLN mapping protocols for breast cancer, using smaller volumes of blue dye may represent a means of optimizing the safety of the procedure without compromising its success.
Background The role of positron emission tomography (PET) scanning in determining the extent of ... more Background The role of positron emission tomography (PET) scanning in determining the extent of disease in patients with breast cancer has not been defined. We investigated the utility of 18F-2-fluoro-2-deoxy-D-glucose (FDG)-PET scanning compared with conventional imaging with computed tomographic scanning and bone scanning in determining the extent of disease in patients with high-risk, operable breast cancer. Methods This was a prospective study
Management of patients with breast cancers < or = 1 cm remains controversial. Reports of i... more Management of patients with breast cancers < or = 1 cm remains controversial. Reports of infrequent nodal metastases in tumors < or = 5 mm has led to suggestions that axillary dissection should be selective, and that tumor characteristics should guide adjuvant therapy. A retrospective review of 290 patients with breast cancer 1 cm in size or smaller from 1989 to 1991 was done. Distant disease-free survival (DDFS) was the primary outcome measure. There were 95 T1a (< or = 5 mm) and 196 T1b (6-10 mm) cancers. Nodal metastases were found in 8 T1a and 26 T1b tumors. Larger size, poorer differentiation, and lymphovascular invasion (LVI) were associated with more nodal metastases, but none of these trends reached statistical significance. The 6-year DDFS was 93% for node-negative and 87% for node-positive patients (P = .02). Overall, breast cancers with poorer differentiation and LVI trended toward a poorer outcome. For patients with node-negative tumors, LVI was associated with a poorer outcome (P = .03). The size of the primary tumor was not predictive of outcome. There were no nodal metastases or recurrences in the 18 patients with microinvasive breast cancer. Lymph node status is the major determinant of outcome in breast cancers 1 cm in size or smaller. Accurate axillary assessment remains crucial in management of small breast cancer.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial demonstrated that tamox... more The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial demonstrated that tamoxifen reduces the incidence of new breast cancers by 49% in women at increased risk for breast cancer development. Tamoxifen does have side effects, however, including marginally increased risks of endometrial cancer and thromboembolic events. In this study, women at increased risk for breast cancer development were offered tamoxifen. Their knowledge of tamoxifen as a chemopreventive agent was assessed, and factors influencing their acceptance of tamoxifen and willingness to take it were determined. Forty-three patients were identified who qualified to take tamoxifen for primary prevention. Patients qualified by having at least a 1.7% 5-year risk of developing breast cancer, the criteria for entry into the NSABP P-1 trial. Patients initially completed questionnaires designed to assess their knowledge of tamoxifen and its associated risks and benefits. Patients were then provided neutral educational sessions and literature delineating the actual risks and benefits of tamoxifen. Subsequently, patients' decisions regarding taking tamoxifen were reassessed. Mean patient age was 52.8 years, with a range of 39 to 74 years. Ten patients (23.2%) qualified based on the presence of lobular carcinoma in situ (LCIS), seven patients (16.3%) qualified based on increased risk secondary to age >60 years, and 26 patients (60.5%) age range 35 to 59 qualified based on risk profiles demonstrating significantly increased risk. Of the total 43 patients, two (4.7%) elected to start taking tamoxifen. Fifteen patients (34.8%) declined immediately, and 26 patients (60.5%) were undecided initially but ultimately declined. Educational sessions did not influence patients' decisions. Fear of side effects, including endometrial cancer, thromboembolic events, and menopausal symptoms, was the most commonly cited reason for declining to take tamoxifen. In this study, the vast majority of patients at increased risk for breast cancer perceived that the risks of taking tamoxifen outweighed the benefits and declined to take it.
Although many questions regarding sentinel lymph node (SLN) biopsy in breast cancer have been ans... more Although many questions regarding sentinel lymph node (SLN) biopsy in breast cancer have been answered by observational studies and, increasingly, by prospective trials, the role of intraoperative SLN assessment remains a matter of debate. Here we report in detail the results of intraoperative SLN assessment by frozen section (FS), with particular attention to variations in sensitivity and yield by histologic subtype, by tumor size, and by other clinicopathologic parameters. Five thousand two hundred ninety-eight consecutive patients with clinical stage T1-3N0 invasive breast carcinoma had SLN biopsy with intraoperative FS at Memorial Sloan Kettering Cancer Center between 1996 and 2004. We report the results of FS by sensitivity (the proportion of all positive SLN detected by FS) and by yield (the proportion of all FS procedures in which the FS was positive). The sensitivity of FS was 61% overall, was higher for invasive duct (ID) than for invasive lobular (IL) cancers (62% vs. 52%; P = 0.006), and was marginally lower for favorable subtypes (46%; P = 0.26). The yield of FS was 21% overall, with no difference between ID and IL cancers (22% vs. 21%; P = 0.49), and with a substantially lower yield for favorable subtypes (3%; P < 0.001). The yield of FS increased with tumor size for ID and IL cancers (P < 0.001), but not for favorable subtypes. For both ID and IL cancers, the sensitivity and yield of FS were significantly higher with younger patient age, increasing tumor size, and lymphovascular invasion. The yield of FS was <10% for all patients with ID or IL tumors < or =1 cm in size who were older than 60 years of age. Among all FS-positive patients, only 45% were identified by the first FS, whereas 91% were cumulatively identified by the first, second, or third FS. For patients with ID and IL cancers, the overall sensitivity of FS is >50%, but the yield of FS is <10% for individuals > or =60 years of age with T1a/b tumors. Intraoperative FS may not be worthwhile for this low-yield subset, especially for patients with invasive breast cancer of favorable type.
We sought to identify the rate of axillary recurrence after sentinel lymph node (SLN) biopsy for ... more We sought to identify the rate of axillary recurrence after sentinel lymph node (SLN) biopsy for breast cancer. SLN biopsy is a new standard of care for axillary lymph node staging in breast cancer. Nevertheless, most validated series of SLN biopsy confirm that the SLN is falsely negative in 5-10% of node-positive cases, and few studies report the rate of axillary local recurrence (LR) for that subset of patients staged by SLN biopsy alone. Through December of 2002, 4008 consecutive SLN biopsy procedures were performed at Memorial Sloan-Kettering Cancer Center for unilateral invasive breast cancer. Patients were categorized in 4 groups: SLN-negative with axillary lymph node dissection (ALND; n = 326), SLN-negative without ALND (n = 2340), SLN-positive with ALND (n = 1132), and SLN-positive without ALND (n = 210). Clinical and pathologic characteristics and follow-up data for each of the 4 cohorts were evaluated with emphasis on patterns of axillary LR. With a median follow-up of 31 months (range, 1-75), axillary LR occurred in 10/4008 (0.25%) patients overall. In 3 cases (0.07%) the axillary LR was the first site of treatment failure, in 4 (0.1%) it was coincident with breast LR, and in 3 (0.07%) it was coincident with distant metastases. Axillary LR was more frequent among the unconventionally treated SLN-positive/no ALND patients than in the other 3 conventionally treated cohorts (1.4% versus 0.18%, P = 0.013). Axillary LR after SLN biopsy, with or without ALND, is a rare event, and this low relapse rate supports wider use of SLN biopsy for breast cancer staging. There is a low-risk subset of SLN-positive patients in whom completion ALND may not be required.
In the United States, identification of the sentinel lymph node (SLN) requires the use of (99m)Tc... more In the United States, identification of the sentinel lymph node (SLN) requires the use of (99m)Tc-labeled colloid, 1% isosulfan blue dye, or both to trace the lymphatic drainage of a given neoplasm. We report our experience with adverse reactions to isosulfan blue dye during SLN mapping in breast cancer. A chart review of the breast cancer SLN database was performed; it included 2392 sequential patients who underwent SLN biopsy involving isosulfan blue dye at Memorial Sloan-Kettering Cancer Center from September 12, 1996, to August 17, 2000. Thirty-nine of 2392 patients (1.6%) had a documented allergic reaction during the mapping procedure. Most reactions (69%) produced urticaria, blue hives, a generalized rash, or pruritus. The incidence of hypotensive reactions was 0.5%. Although anaphylaxis after the injection of isosulfan blue dye is rare, this article highlights the need to suspect anaphylaxis when hemodynamic instability occurs after the injection of this compound. Our experience indicates that bronchospasm and respiratory compromise are unusual and that most patients do not require emergent intubation and can be managed with short-term pressor support. In addition, our data indicate that patients with a sulfa allergy do not display a cross-sensitivity to isosulfan blue dye. We report the largest single-institution review of adverse reactions to injection of isosulfan blue dye during sentinel lymph node mapping in breast cancer. Bronchospasm and respiratory compromise are unusual, and most patients can be treated with short-term pressor support. Patients with a sulfa allergy do not display a cross-sensitivity to isosulfan blue dye.
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