Case 24-2005 — A 58-Year-Old Woman with Early-Stage Estrogen-Receptor–Positive Breast Cancer
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《新英格兰医药杂志》
Presentation of Case
A 58-year-old woman was seen in the multidisciplinary breast-cancer clinic of this hospital for management of early-stage breast cancer.
One month earlier, a routine screening mammogram at another facility revealed an ill-defined mass, approximately 15 to 20 mm in diameter, associated with calcifications in the lower inner quadrant of the right breast. The mass had not been present on a mammogram obtained two and a half years earlier. An ultrasonographic examination performed at this hospital 12 days after routine mammography showed a hypoechoic mass at the 3 o'clock position, measuring 1.2 cm in diameter. Two days later an ultrasonographically guided core biopsy was performed. Pathological examination of the specimen revealed invasive ductal carcinoma; as evaluated by immunohistochemistry, the tumor cells expressed amounts of both estrogen-receptor protein and progesterone-receptor protein; the expression of HER2/neu protein was 2+ out of 3+, but there was no amplification of the HER2/neu gene on fluorescence in situ hybridization (FISH). The patient chose to have breast-conserving therapy and was referred to the breast-cancer clinic.
Five years earlier, a papilloma had been excised from the patient's right breast, and 24 years earlier a fibroadenoma had been removed from her left breast. Menarche had occurred when she was 13 years of age; she was gravida 2, para 2, with a first pregnancy at the age of 27. She had used oral contraceptives in the past for four years. Menopause occurred at the age of 51, and she had never used hormone-replacement therapy. One year before the current evaluation, a computed tomographic (CT) scan of the abdomen that had been performed for evaluation of diverticulitis showed a left adnexal mass; left salpingo-oophorectomy was performed and revealed an ovarian fibroma. The patient had hypertension, hypercholesterolemia, hypothyroidism, and osteopenia. She was taking hydrochlorothiazide, atorvastatin, levothyroxine, a multivitamin, calcium, and vitamin D. A maternal aunt had received a diagnosis of breast cancer when she was in her 30s, and the patient's mother had died from a brain tumor at 39 years of age. Her father was alive and healthy at 84 years of age.
On physical examination, the patient appeared well, and her vital signs were normal. There was no lymphadenopathy. The lungs were clear, the heart sounds were normal, and the abdomen was soft with no masses or organomegaly. The breasts were symmetric with no suspicious nodularity in either breast, and there were no skin or nipple changes. There was no edema in her lower extremities. The results of a complete blood count and the levels of electrolytes, calcium, creatinine, urea nitrogen, protein, albumin, globulin, and bilirubin were all in the normal range.
Management options were discussed.
Differential Diagnosis
Dr. Paula D. Ryan: May we review the radiologic studies?
Dr. Daniel B. Kopans: The craniocaudal mammographic view (Figure 1A) reveals an ill-defined mass with very small associated calcifications. In the mediolateral-oblique view, the lesion is in the inferior portion of the breast, close to the chest wall. These findings are also seen in the straight lateral view. Greater detail is seen in the magnified view. (Figure 1A, inset). The fine, white specks are clustered calcifications; these are typically found in the intraductal portion of a cancer. There is an ill-defined mass associated with the calcifications in the lateral projection. These findings are highly suggestive of invasive ductal carcinoma with an intraductal component. The core biopsy confirmed the presence of an invasive ductal carcinoma.
Figure 1. Radiologic Studies of the Breast and Lumpectomy Specimen.
The craniocaudal view from the mammogram reveals an ill-defined mass with very small associated calcifications in the inferior portion of the breast (Panel A), close to the chest wall (arrow). Magnification shows greater detail (Panel A, inset). The fine, white specks are clustered calcifications; these are typically found in the intraductal portion of a cancer. The radiograph of the specimen obtained by lumpectomy (Panel B) confirms the presence of both the microcalcifications and the tumor mass (arrow).
Dr. Ryan: This postmenopausal patient presented with a small, nonpalpable breast cancer that was detected on mammography. The two issues in the management of early-stage breast cancer in a patient such as this are local control of the tumor in the breast and regional lymph nodes and systemic control of microscopic tumor that has already spread outside the breast.
A major decision that this patient faced was whether to undergo a mastectomy or to pursue breast-conserving therapy. Studies with 20-year follow-up have found that lumpectomy with irradiation is a safe and effective treatment for early-stage breast cancer.1,2 This procedure coupled with sentinel-lymph-node biopsy has been determined to be a safe and accurate method of screening axillary lymph nodes for metastases in early-stage breast cancer, with an overall accuracy of 97 percent, sensitivity of 92 percent, and specificity of 100 percent.3 Lumpectomy with sentinel-lymph-node mapping was offered to this patient; she chose this option rather than mastectomy.
This treatment is usually accompanied by systemic therapy with either hormones or their congeners or chemotherapy. Several pathological criteria are used to guide recommendations for systemic treatment of breast cancer. These include tumor size, tumor grade, the status of sentinel or axillary lymph nodes, and the presence or absence of the estrogen receptor, progesterone receptor, and HER2/neu gene amplification. The core biopsy revealed that this patient's tumor expressed both estrogen and progesterone receptors and did not have HER2/neu amplification. On the basis of this information, I considered hormonal therapy for her, but other factors, such as the tumor size, tumor grade, and status of the axillary lymph nodes, needed to be determined on the basis of evaluation of the lumpectomy specimen before a final recommendation for systemic treatment was possible.
Pathological Discussion
Dr. Dennis C. Sgroi: When a lumpectomy is performed, the specimen is submitted for radiography before the pathological examination is performed. Dr. Kopans, may we see the specimen radiograph?
Dr. Kopans: As part of the lumpectomy procedure, needle localization was carried out. In cases such as this, in which the surgeon is unable to palpate the lesion, we place a guide wire to direct the surgeon to the lesion, using ultrasonographic, mammographic, or CT guidance. First, a needle is positioned into or alongside the lesion. The wire is then passed through the needle and into the desired location, so that it is stabilized in the tissue. The surgeon can then follow the wire down to the lesion and remove it.
The specimen radiograph (Figure 1B) recapitulates what was seen on the mammogram. It shows an ill-defined mass that is consistent with an invasive cancer and the calcifications that presumably are in the in situ portion of this tumor.
Dr. Sgroi: Examination of the lumpectomy specimen from the right breast (Figure 2A) revealed an invasive ductal carcinoma, 2.3 cm by 1.2 cm by 1.2 cm, that consisted of medium-sized, malignant epithelial cells infiltrating fibroadipose tissue as cohesive cords and nests, with no evidence of lymphatic vessel invasion. Associated with the invasive carcinoma was ductal carcinoma in situ harboring microcalcifications (Figure 2B). The tumor was moderately differentiated (grade 2 of 3), with low-to-moderate mitotic activity. More than 60 percent of the tumor nuclei showed moderate-to-intense expression of both estrogen receptor and progesterone receptor, as determined by immunohistochemical staining (Figure 2C). The tumor cells showed intermediate expression (2+ of 3+) of HER2/neu protein as determined by immunohistochemical analysis, but lacked HER2/neu gene amplification by FISH. The oncoprotein encoded by the HER2/neu oncogene is a member of the family of epidermal growth factor receptors called receptor tyrosine kinases. If there is either no protein expression or high-level expression, FISH is not needed. However, in cases such as this, with intermediate levels of protein expression, amplification must be confirmed or ruled out by FISH. A biopsy specimen of a sentinel node was negative for metastatic carcinoma.
Figure 2. Histopathological Features of the Resected Breast Cancer.
A tissue section from the tumor, stained with hematoxylin and eosin, reveals nests and cords of malignant ductal epithelial cells invading fibroadipose tissue (Panel A) and associated ductal carcinoma in situ harboring microcalcifications (Panel B). The malignant ductal epithelial cells show nuclear expression of estrogen-receptor protein (Panel C, immunoperoxidase stain).
The clinicopathological factors that are currently used for risk stratification often inaccurately predict the clinical course of breast cancer. Consequently, efforts are being made to identify new biomarkers that will assist providers in selecting optimal clinical-management strategies for a patient such as the one in this case. Gene-expression–profile analysis with DNA microarrays is used in the classification of human cancers because it provides a comprehensive molecular analysis of genes expressed by the tumors. In microarray analysis, nucleic acid polymer probes are immobilized on a solid surface; fluorescent-labeled RNA from tumor samples is then layered on the microarray, and RNA molecules bind to complementary gene sequences. Thousands of genes from human tumor samples can be assessed simultaneously, making it possible to detect differential gene-expression patterns, or signatures, that distinguish them from normal tissues, other types of tumors, and tumors with a different prognosis or response to treatment.
Studies of gene-expression profiles based on microarray analysis in breast cancers have shown that morphologically similar cancers in different patients can be made up of distinct subtypes when analyzed at the molecular level.4,5,6,7 Furthermore,6,8 the pattern of genes expressed in these specific subtypes of cancer is likely to be representative of the molecular pathways driving malignant transformation. Recent studies linking gene-expression profiles to clinical outcome have shown that the potential for distant metastasis and the probability of overall survival can be predicted on the basis of the biologic characteristics of the primary breast tumor.9 Several retrospective studies of breast cancer have shown that analysis of gene-expression profiles can identify prognostic categories that may guide treatment choices more effectively than available clinicopathological prognostic tools.10,11,12,13,14
Three studies in which distinct methods were used have suggested that gene-expression analysis may be useful in identifying prognostic markers for breast cancer. In one study,10 a 70-gene signature assessed by microarray analysis effectively stratified a large group of premenopausal patients with stage I or II breast cancer into a subgroup of patients with a good prognosis and a subgroup with a poor prognosis. Two studies13,15,16 addressed the use of gene-expression analysis to predict recurrence of lymph-node–negative breast cancer that had been treated with tamoxifen. In one study, the expression ratio of two genes, assessed with the use of reverse-transcriptase–quantitative polymerase-chain-reaction (RT-QPCR) analysis of paraffin-embedded tissue, predicted the likelihood of recurrence in a small cohort of patients with node-negative breast cancer treated with tamoxifen alone.13,15,16 Another study14 analyzed a set of 21 genes, using RT-QPCR on paraffin-embedded tissue to generate a "recurrence score," which effectively predicted which patients would remain free from distant recurrence. Although these gene-expression signatures or recurrence scores may not be completely independent of tumor grade, they lack the subjectivity and interobserver variability associated with current tumor-grading classification schemes. The 21-gene signature test is commercially available.
Discussion of Management
Dr. Ryan: As summarized by Dr. Sgroi, this patient had a breast cancer of pathological stage T2N0, according to the American Joint Committee on Cancer staging criteria for breast cancer, with a tumor size of 2.3 cm, grade II, and no tumor identified in the sentinel lymph node. The tumor cells were positive for estrogen and progesterone receptors, and negative for HER2/neu amplification. At this point, we needed to decide on the optimal systemic therapy for this patient.
Adjuvant tamoxifen therapy in a postmenopausal woman with estrogen-receptor–positive breast cancer provides an annual reduction in the chance of death from breast cancer of 31 percent, whereas chemotherapy provides a 20 percent reduction.17 In a postmenopausal patient such as this with breast cancer that is node-negative and with a baseline risk of recurrence that is low, the benefit of adding systemic chemotherapy may be quite small, especially after factoring in the toxicity of chemotherapy as compared with tamoxifen.
There are published guidelines from the National Institutes of Health (NIH) and the St. Gallen consensus conferences on the adjuvant treatment of early-stage breast cancer that can help clinicians in their recommendations for chemotherapy, but these guidelines differ in whether chemotherapy is recommended or not, depending on the size of the tumor and other histopathological criteria.18,19 With the use of the 70-gene prognosis signature described by Dr. Sgroi, the high-risk groups defined by either the NIH or the St. Gallen criteria included some patients who had a good-prognosis signature, and conversely, the low-risk groups identified by these criteria included some patients with a poor-prognosis signature.11
The patient in this case had a tumor with predominantly good prognostic features with the exception of the size. According to the NIH criteria, for a tumor size of 2.3 cm, chemotherapy would be recommended, in addition to tamoxifen. Chemotherapy, however, would provide a very small additional benefit in this case. For example, on the basis of estimates by Adjuvant! (www.adjuvantonline.com),20 a computerized model that calculates the risk of recurrence and death in women with invasive breast cancer with and without adjuvant systemic therapy, chemotherapy would provide an additional benefit of 3.4 percentage points as compared with tamoxifen alone for recurrence and a 1.2 percentage point improvement in survival at 10 years.20 This case is an example of one in which novel biomarkers that predict clinical outcome would assist in the decision about whether to recommend hormonal therapy alone or with chemotherapy.
Finally, for patients for whom hormonal treatment is recommended, an aromatase inhibitor is another option. The Arimidex, Tamoxifen, Alone or in Combination Trial found an absolute benefit in terms of overall disease-free survival of the aromatase inhibitor anastrozole over tamoxifen of 2.4 percent at four years among postmenopausal women with invasive breast cancer in a randomized trial of these drugs given immediately after surgical treatment.21 The Intergroup Exemestane Study assigned postmenopausal patients after two to three years of tamoxifen therapy at random either to complete five years of therapy with tamoxifen or to receive exemestane to complete the five years. The hazard ratio for disease-free survival was 0.68 (P<0.001) in favor of exemestane therapy.22 Among women who had completed at least five years of adjuvant tamoxifen therapy, letrozole was associated with an improved disease-free survival rate at four years (93 percent) as compared with placebo (87 percent).23
With these data, a recent technology assessment from the American Society of Clinical Oncologists suggested that adjuvant therapy for postmenopausal women with hormone-receptor–positive breast cancer should include an aromatase inhibitor.24 What remains to be clarified is the appropriate sequence, timing, and duration of adjuvant hormonal therapy. An interesting question is whether novel biomarkers identified by molecular profiling of tumors will also help guide our decision making with respect to hormonal therapy. If we can determine and validate a biomarker for tamoxifen resistance, then specific patients may be more appropriate candidates to receive an aromatase inhibitor at their initial diagnosis.
The patient under discussion recovered well from lumpectomy and sentinel-lymph-node biopsy. After a discussion regarding the benefit of chemotherapy as compared with endocrine therapy alone, the decision was made to proceed with treatment with anastrozole alone. The patient received adjuvant radiation therapy and is presently doing well, one year after she received the diagnosis of breast cancer.
Anatomical Diagnosis
Invasive ductal carcinoma, T2N0, positive for estrogen receptor and progesterone receptor, negative for HER2/neu amplification.
Dr. Sgroi reports that he is a named coinventor on a pending patent application to use the HOXB13:IL17BR expression ratio to ascertain breast-cancer prognosis. The technology is co-owned by Massachusetts General Hospital and Arcturus Bioscience; Massachusetts General Hospital has licensed its rights in the patent to Arcturus.
Source Information
From the Departments of Hematology and Oncology (P.D.R.), Radiology (D.B.K.), and Pathology (D.C.S.), Massachusetts General Hospital; and the Departments of Medicine (P.D.R.), Radiology (D.B.K.), and Pathology (D.C.S.), Harvard Medical School.
References
Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227-1232.
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-1241.
Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546-553.
Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999;286:531-537.
Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869-10874.
Ma XJ, Salunga R, Tuggle JT, et al. Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci U S A 2003;100:5974-5979.
Hedenfalk I, Duggan D, Chen Y, et al. Gene-expression profiles in hereditary breast cancer. N Engl J Med 2001;344:539-548.
Sgroi DC, Teng S, Robinson G, LeVangie R, Hudson JR Jr, Elkahloun AG. In vivo gene expression profile analysis of human breast cancer progression. Cancer Res 1999;59:5656-5661.
Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003;33:49-54.
van't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:530-536.
van de Vijver MJ, He YD, van't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999-2009.
Chang JC, Wooten EC, Tsimelzon A, et al. Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 2003;362:362-369.
Ma XJ, Wang Z, Ryan PD, et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 2004;5:607-616.
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817-2826.
Sgroi DC, Ma XJ, Ryan P, et al. Discovery of new gene expression predictors for adjuvant tamoxifen outcome for breast cancer patients. J Clin Oncol 2004;22:Suppl:14S-14S. abstract.
Sgroi DC, Haber DA, Ryan PD, Ma XJ, Erlanger MG. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 2004;6:445-445.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-1717.
Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 2003;21:3357-3365.
Eifel P, Axelson JA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst 2001;93:979-989.
Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 2005;23:2716-2725.
Baum M, Buzdar A, Cuzick J, et al. The ATAC. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 2003;98:1802-1810.
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081-1092.
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793-1802.
Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005;23:619-629.(Paula D. Ryan, M.D., Ph.D)
A 58-year-old woman was seen in the multidisciplinary breast-cancer clinic of this hospital for management of early-stage breast cancer.
One month earlier, a routine screening mammogram at another facility revealed an ill-defined mass, approximately 15 to 20 mm in diameter, associated with calcifications in the lower inner quadrant of the right breast. The mass had not been present on a mammogram obtained two and a half years earlier. An ultrasonographic examination performed at this hospital 12 days after routine mammography showed a hypoechoic mass at the 3 o'clock position, measuring 1.2 cm in diameter. Two days later an ultrasonographically guided core biopsy was performed. Pathological examination of the specimen revealed invasive ductal carcinoma; as evaluated by immunohistochemistry, the tumor cells expressed amounts of both estrogen-receptor protein and progesterone-receptor protein; the expression of HER2/neu protein was 2+ out of 3+, but there was no amplification of the HER2/neu gene on fluorescence in situ hybridization (FISH). The patient chose to have breast-conserving therapy and was referred to the breast-cancer clinic.
Five years earlier, a papilloma had been excised from the patient's right breast, and 24 years earlier a fibroadenoma had been removed from her left breast. Menarche had occurred when she was 13 years of age; she was gravida 2, para 2, with a first pregnancy at the age of 27. She had used oral contraceptives in the past for four years. Menopause occurred at the age of 51, and she had never used hormone-replacement therapy. One year before the current evaluation, a computed tomographic (CT) scan of the abdomen that had been performed for evaluation of diverticulitis showed a left adnexal mass; left salpingo-oophorectomy was performed and revealed an ovarian fibroma. The patient had hypertension, hypercholesterolemia, hypothyroidism, and osteopenia. She was taking hydrochlorothiazide, atorvastatin, levothyroxine, a multivitamin, calcium, and vitamin D. A maternal aunt had received a diagnosis of breast cancer when she was in her 30s, and the patient's mother had died from a brain tumor at 39 years of age. Her father was alive and healthy at 84 years of age.
On physical examination, the patient appeared well, and her vital signs were normal. There was no lymphadenopathy. The lungs were clear, the heart sounds were normal, and the abdomen was soft with no masses or organomegaly. The breasts were symmetric with no suspicious nodularity in either breast, and there were no skin or nipple changes. There was no edema in her lower extremities. The results of a complete blood count and the levels of electrolytes, calcium, creatinine, urea nitrogen, protein, albumin, globulin, and bilirubin were all in the normal range.
Management options were discussed.
Differential Diagnosis
Dr. Paula D. Ryan: May we review the radiologic studies?
Dr. Daniel B. Kopans: The craniocaudal mammographic view (Figure 1A) reveals an ill-defined mass with very small associated calcifications. In the mediolateral-oblique view, the lesion is in the inferior portion of the breast, close to the chest wall. These findings are also seen in the straight lateral view. Greater detail is seen in the magnified view. (Figure 1A, inset). The fine, white specks are clustered calcifications; these are typically found in the intraductal portion of a cancer. There is an ill-defined mass associated with the calcifications in the lateral projection. These findings are highly suggestive of invasive ductal carcinoma with an intraductal component. The core biopsy confirmed the presence of an invasive ductal carcinoma.
Figure 1. Radiologic Studies of the Breast and Lumpectomy Specimen.
The craniocaudal view from the mammogram reveals an ill-defined mass with very small associated calcifications in the inferior portion of the breast (Panel A), close to the chest wall (arrow). Magnification shows greater detail (Panel A, inset). The fine, white specks are clustered calcifications; these are typically found in the intraductal portion of a cancer. The radiograph of the specimen obtained by lumpectomy (Panel B) confirms the presence of both the microcalcifications and the tumor mass (arrow).
Dr. Ryan: This postmenopausal patient presented with a small, nonpalpable breast cancer that was detected on mammography. The two issues in the management of early-stage breast cancer in a patient such as this are local control of the tumor in the breast and regional lymph nodes and systemic control of microscopic tumor that has already spread outside the breast.
A major decision that this patient faced was whether to undergo a mastectomy or to pursue breast-conserving therapy. Studies with 20-year follow-up have found that lumpectomy with irradiation is a safe and effective treatment for early-stage breast cancer.1,2 This procedure coupled with sentinel-lymph-node biopsy has been determined to be a safe and accurate method of screening axillary lymph nodes for metastases in early-stage breast cancer, with an overall accuracy of 97 percent, sensitivity of 92 percent, and specificity of 100 percent.3 Lumpectomy with sentinel-lymph-node mapping was offered to this patient; she chose this option rather than mastectomy.
This treatment is usually accompanied by systemic therapy with either hormones or their congeners or chemotherapy. Several pathological criteria are used to guide recommendations for systemic treatment of breast cancer. These include tumor size, tumor grade, the status of sentinel or axillary lymph nodes, and the presence or absence of the estrogen receptor, progesterone receptor, and HER2/neu gene amplification. The core biopsy revealed that this patient's tumor expressed both estrogen and progesterone receptors and did not have HER2/neu amplification. On the basis of this information, I considered hormonal therapy for her, but other factors, such as the tumor size, tumor grade, and status of the axillary lymph nodes, needed to be determined on the basis of evaluation of the lumpectomy specimen before a final recommendation for systemic treatment was possible.
Pathological Discussion
Dr. Dennis C. Sgroi: When a lumpectomy is performed, the specimen is submitted for radiography before the pathological examination is performed. Dr. Kopans, may we see the specimen radiograph?
Dr. Kopans: As part of the lumpectomy procedure, needle localization was carried out. In cases such as this, in which the surgeon is unable to palpate the lesion, we place a guide wire to direct the surgeon to the lesion, using ultrasonographic, mammographic, or CT guidance. First, a needle is positioned into or alongside the lesion. The wire is then passed through the needle and into the desired location, so that it is stabilized in the tissue. The surgeon can then follow the wire down to the lesion and remove it.
The specimen radiograph (Figure 1B) recapitulates what was seen on the mammogram. It shows an ill-defined mass that is consistent with an invasive cancer and the calcifications that presumably are in the in situ portion of this tumor.
Dr. Sgroi: Examination of the lumpectomy specimen from the right breast (Figure 2A) revealed an invasive ductal carcinoma, 2.3 cm by 1.2 cm by 1.2 cm, that consisted of medium-sized, malignant epithelial cells infiltrating fibroadipose tissue as cohesive cords and nests, with no evidence of lymphatic vessel invasion. Associated with the invasive carcinoma was ductal carcinoma in situ harboring microcalcifications (Figure 2B). The tumor was moderately differentiated (grade 2 of 3), with low-to-moderate mitotic activity. More than 60 percent of the tumor nuclei showed moderate-to-intense expression of both estrogen receptor and progesterone receptor, as determined by immunohistochemical staining (Figure 2C). The tumor cells showed intermediate expression (2+ of 3+) of HER2/neu protein as determined by immunohistochemical analysis, but lacked HER2/neu gene amplification by FISH. The oncoprotein encoded by the HER2/neu oncogene is a member of the family of epidermal growth factor receptors called receptor tyrosine kinases. If there is either no protein expression or high-level expression, FISH is not needed. However, in cases such as this, with intermediate levels of protein expression, amplification must be confirmed or ruled out by FISH. A biopsy specimen of a sentinel node was negative for metastatic carcinoma.
Figure 2. Histopathological Features of the Resected Breast Cancer.
A tissue section from the tumor, stained with hematoxylin and eosin, reveals nests and cords of malignant ductal epithelial cells invading fibroadipose tissue (Panel A) and associated ductal carcinoma in situ harboring microcalcifications (Panel B). The malignant ductal epithelial cells show nuclear expression of estrogen-receptor protein (Panel C, immunoperoxidase stain).
The clinicopathological factors that are currently used for risk stratification often inaccurately predict the clinical course of breast cancer. Consequently, efforts are being made to identify new biomarkers that will assist providers in selecting optimal clinical-management strategies for a patient such as the one in this case. Gene-expression–profile analysis with DNA microarrays is used in the classification of human cancers because it provides a comprehensive molecular analysis of genes expressed by the tumors. In microarray analysis, nucleic acid polymer probes are immobilized on a solid surface; fluorescent-labeled RNA from tumor samples is then layered on the microarray, and RNA molecules bind to complementary gene sequences. Thousands of genes from human tumor samples can be assessed simultaneously, making it possible to detect differential gene-expression patterns, or signatures, that distinguish them from normal tissues, other types of tumors, and tumors with a different prognosis or response to treatment.
Studies of gene-expression profiles based on microarray analysis in breast cancers have shown that morphologically similar cancers in different patients can be made up of distinct subtypes when analyzed at the molecular level.4,5,6,7 Furthermore,6,8 the pattern of genes expressed in these specific subtypes of cancer is likely to be representative of the molecular pathways driving malignant transformation. Recent studies linking gene-expression profiles to clinical outcome have shown that the potential for distant metastasis and the probability of overall survival can be predicted on the basis of the biologic characteristics of the primary breast tumor.9 Several retrospective studies of breast cancer have shown that analysis of gene-expression profiles can identify prognostic categories that may guide treatment choices more effectively than available clinicopathological prognostic tools.10,11,12,13,14
Three studies in which distinct methods were used have suggested that gene-expression analysis may be useful in identifying prognostic markers for breast cancer. In one study,10 a 70-gene signature assessed by microarray analysis effectively stratified a large group of premenopausal patients with stage I or II breast cancer into a subgroup of patients with a good prognosis and a subgroup with a poor prognosis. Two studies13,15,16 addressed the use of gene-expression analysis to predict recurrence of lymph-node–negative breast cancer that had been treated with tamoxifen. In one study, the expression ratio of two genes, assessed with the use of reverse-transcriptase–quantitative polymerase-chain-reaction (RT-QPCR) analysis of paraffin-embedded tissue, predicted the likelihood of recurrence in a small cohort of patients with node-negative breast cancer treated with tamoxifen alone.13,15,16 Another study14 analyzed a set of 21 genes, using RT-QPCR on paraffin-embedded tissue to generate a "recurrence score," which effectively predicted which patients would remain free from distant recurrence. Although these gene-expression signatures or recurrence scores may not be completely independent of tumor grade, they lack the subjectivity and interobserver variability associated with current tumor-grading classification schemes. The 21-gene signature test is commercially available.
Discussion of Management
Dr. Ryan: As summarized by Dr. Sgroi, this patient had a breast cancer of pathological stage T2N0, according to the American Joint Committee on Cancer staging criteria for breast cancer, with a tumor size of 2.3 cm, grade II, and no tumor identified in the sentinel lymph node. The tumor cells were positive for estrogen and progesterone receptors, and negative for HER2/neu amplification. At this point, we needed to decide on the optimal systemic therapy for this patient.
Adjuvant tamoxifen therapy in a postmenopausal woman with estrogen-receptor–positive breast cancer provides an annual reduction in the chance of death from breast cancer of 31 percent, whereas chemotherapy provides a 20 percent reduction.17 In a postmenopausal patient such as this with breast cancer that is node-negative and with a baseline risk of recurrence that is low, the benefit of adding systemic chemotherapy may be quite small, especially after factoring in the toxicity of chemotherapy as compared with tamoxifen.
There are published guidelines from the National Institutes of Health (NIH) and the St. Gallen consensus conferences on the adjuvant treatment of early-stage breast cancer that can help clinicians in their recommendations for chemotherapy, but these guidelines differ in whether chemotherapy is recommended or not, depending on the size of the tumor and other histopathological criteria.18,19 With the use of the 70-gene prognosis signature described by Dr. Sgroi, the high-risk groups defined by either the NIH or the St. Gallen criteria included some patients who had a good-prognosis signature, and conversely, the low-risk groups identified by these criteria included some patients with a poor-prognosis signature.11
The patient in this case had a tumor with predominantly good prognostic features with the exception of the size. According to the NIH criteria, for a tumor size of 2.3 cm, chemotherapy would be recommended, in addition to tamoxifen. Chemotherapy, however, would provide a very small additional benefit in this case. For example, on the basis of estimates by Adjuvant! (www.adjuvantonline.com),20 a computerized model that calculates the risk of recurrence and death in women with invasive breast cancer with and without adjuvant systemic therapy, chemotherapy would provide an additional benefit of 3.4 percentage points as compared with tamoxifen alone for recurrence and a 1.2 percentage point improvement in survival at 10 years.20 This case is an example of one in which novel biomarkers that predict clinical outcome would assist in the decision about whether to recommend hormonal therapy alone or with chemotherapy.
Finally, for patients for whom hormonal treatment is recommended, an aromatase inhibitor is another option. The Arimidex, Tamoxifen, Alone or in Combination Trial found an absolute benefit in terms of overall disease-free survival of the aromatase inhibitor anastrozole over tamoxifen of 2.4 percent at four years among postmenopausal women with invasive breast cancer in a randomized trial of these drugs given immediately after surgical treatment.21 The Intergroup Exemestane Study assigned postmenopausal patients after two to three years of tamoxifen therapy at random either to complete five years of therapy with tamoxifen or to receive exemestane to complete the five years. The hazard ratio for disease-free survival was 0.68 (P<0.001) in favor of exemestane therapy.22 Among women who had completed at least five years of adjuvant tamoxifen therapy, letrozole was associated with an improved disease-free survival rate at four years (93 percent) as compared with placebo (87 percent).23
With these data, a recent technology assessment from the American Society of Clinical Oncologists suggested that adjuvant therapy for postmenopausal women with hormone-receptor–positive breast cancer should include an aromatase inhibitor.24 What remains to be clarified is the appropriate sequence, timing, and duration of adjuvant hormonal therapy. An interesting question is whether novel biomarkers identified by molecular profiling of tumors will also help guide our decision making with respect to hormonal therapy. If we can determine and validate a biomarker for tamoxifen resistance, then specific patients may be more appropriate candidates to receive an aromatase inhibitor at their initial diagnosis.
The patient under discussion recovered well from lumpectomy and sentinel-lymph-node biopsy. After a discussion regarding the benefit of chemotherapy as compared with endocrine therapy alone, the decision was made to proceed with treatment with anastrozole alone. The patient received adjuvant radiation therapy and is presently doing well, one year after she received the diagnosis of breast cancer.
Anatomical Diagnosis
Invasive ductal carcinoma, T2N0, positive for estrogen receptor and progesterone receptor, negative for HER2/neu amplification.
Dr. Sgroi reports that he is a named coinventor on a pending patent application to use the HOXB13:IL17BR expression ratio to ascertain breast-cancer prognosis. The technology is co-owned by Massachusetts General Hospital and Arcturus Bioscience; Massachusetts General Hospital has licensed its rights in the patent to Arcturus.
Source Information
From the Departments of Hematology and Oncology (P.D.R.), Radiology (D.B.K.), and Pathology (D.C.S.), Massachusetts General Hospital; and the Departments of Medicine (P.D.R.), Radiology (D.B.K.), and Pathology (D.C.S.), Harvard Medical School.
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