TY - JOUR
AU1 - Carr, John Alfred
AU2 - Havstad, Suzanne
AU3 - Zarbo, Richard J.
AU4 - Divine, George
AU5 - Mackowiak, Pat
AU6 - Velanovich, Vic
AB - HypothesisAmplification of the HER-2/neuoncogene in 25% of breast cancers is associated with a shortened disease-free survival.DesignRetrospective analysis of a patient population referred to a tertiary care facility for HER-2/neutesting. The mean follow-up was 56 months.SettingLarge, urban, tertiary care hospital.PatientsFrom 1995 to 1999, a consecutive sample of 190 patients with breast cancer had tissue samples tested for overexpression of the cell surface oncoprotein by immunostaining (IM) or amplification of the HER-2/neuoncogene by fluorescence in situ hybridization or both. Forty-nine subjects were excluded because they had tissue samples tested at our institution but received their treatment elsewhere. All patients tested for HER-2/neuafter diagnosis with breast cancer in 1999 (n = 47) were excluded from analysis because of short follow-up time. One patient was excluded who had in situ ductal carcinoma. The remaining 93 patients were analyzed.ResultsOf 93 patients, 40 (43%) had gene amplification. Overall, patients with oncogene amplification had a shorter median disease-free interval (22 months) compared with controls (40 months) (P= .003). Analysis by the Cox regression model showed that the HER-2/neustatus remained significantly associated with time to relapse even after adjusting for age and tumor grade (P= .002; adjusted relative risk, 2.4; 95% confidence interval, 1.4-4.4). No association was found between gene amplification and tumor grade (P= .98), estrogen/progesterone receptor status (P= .29 and P= .43, respectively), or lymph node status (P= .98). Seventy-two patients (77%) eventually had disease recurrence, with 18 (25%) of these recurring locally.ConclusionsThe HER-2/neuoncogene is an independent prognostic indicator of a subset of breast cancers that are at high risk of early recurrence, regardless of tumor grade, estrogen/progesterone receptor status, and lymph node status. Patients amplifying the HER-2/neuoncogene have a shorter disease-free survival than patients without the oncogene.IN 1985, the HER-2/neuoncogene was isolated independently by 2 separate groups, which they named HER-2and c-erbB-2.Further analysis revealed the 2 genes to be the same,and it was renamed HER-2/neu. The gene encodes a transmembrane tyrosine kinase, which has homology with, but is distinct from epidermal growth factor receptor. The exact function of this kinase is unknown, but based on its close homology with epidermal growth factor receptor, it may function as a cellular receptor for an undiscovered growth factor. Great interest is now focused on determining the prognostic significance of the presence of this oncogene in breast tumors.Several preliminary reports have documented that breast cancers with HER-2/neuamplification tend to have earlier relapse and shorter overall survival.Retrospective data analysis support the incorporation of doxorubicin as part of adjuvant therapy for patients with breast cancer with HER-2/neuamplification,but it is still unknown if such therapy is beneficial. Moreover, it is unknown if closer surveillance and more frequent clinical examinations will improve survival.Since HER-2/neuamplification is present in 25% to 40% of breast cancers,the potential impact of this tumor marker as a prognostic tool would be profound if it can be shown to have a major effect on the clinical course of the tumor. To better understand its clinical role, a retrospective study of a consecutive sample population was performed at a single, large, tertiary care referral center to determine if there was a significant difference in the disease-free interval or recurrence rate between patients positive and negative for HER-2/neu.PATIENTS AND METHODSFrom 1995 to 1999, 190 patients with breast cancer had tissue from the original surgical specimen tested for amplification of the HER-2/neuoncogene or overexpression of the gene product. Samples were directed for testing by the Breast Tumor Board Consensus at the Henry Ford Hospital, Detroit, Mich, or oncologists outside the institution for immunostaining (IM) to allow determination of protein overexpression and possible therapeutic use of trastuzumab (Herceptin; Genentech, San Francisco, Calif). Samples were also tested by fluorescence in situ hybridization (FISH) to gain prognostic information. Most patients had tissue samples initially tested for the HER-2/neugene product by IM, and if results were strongly positive, no further testing was performed. If the initial staining was indeterminate, the sample was tested by FISH for further characterization. Fluorescence in situ hybridization was the only technique used in 31 cases during the institution's early experience. All samples were then interpreted by one surgical pathologist (R.J.Z.).From the 190 original patients, 49 were excluded because they had tissue samples tested at our institution but received treatment elsewhere. All patients tested for HER-2/neuafter diagnosis with breast cancer in 1999 (n = 47) were excluded from analysis because of short follow-up time. One patient was excluded who had only ductal carcinoma in situ. This left 93 patients who met study criteria. Patients were found to meet study criteria if they received their care at our institution and data were available to assess known prognostic variables (tumor size, grade, lymph node, and estrogen/progesterone receptor [ER/PR] status). Forty patients (43%) were determined to have amplification of the oncogene or overexpression of the gene product, while 53 patients (57%) did not. These 2 patient groups were similar with respect to age, race, histologic type of breast cancer, American Joint Committee on Cancer TNM stage, lymph node status, ER/PR status, tumor grade, and initial therapeutic modalities (Table 1). Only patients with invasive carcinoma were included. Since chemotherapeutic regimens are standardized at our institution, the initial chemotherapy given to all patients had minimal variation. The disease-free interval after initial therapy and the recurrence rate were determined for 83 of 93 patients (the exact length of remission could not be determined in 10 patients). The tumor size, lymph node status, ER/PR status, histologic type, and tumor grade were determined from the surgical resection specimen in 88 of 93 patients.Relationship of Prognostic Variable to HER-2/neu*Tumor Size†Patients, No. (%) (N = 93)Positive for HER-2, No. (%)Odds Ratio (95% CI)T130 (32)11 (37). . .T237 (40)17 (46)1.5 (0.5-3.9)T310 (11)2 (20)0.4 (0.1-2.4)T411 (12)9 (82)7.8 (1.4-42.7)TX5 (5)1 (20). . .ReceptorsER+49 (53)19 (39)0.6 (0.3-1.5)ER−‡40 (47)20 (50). . .PR+47 (51)19 (40)0.7 (0.3-1.7)PR−§41 (49)20 (49). . .Lymph nodesax LN+58 (63)25 (43)1.0 (0.4-2.4)ax LN−∥30 (32)13 (43). . .NX5 (5)2 (40). . .Tumor gradeG222 (24)11 (50)1.1 (0.4-2.9)G3¶52 (57)25 (48). . .No grade18 (19)4 (22). . .*CI indicates confidence interval; ellipses, not applicable; ER, estrogen receptor; +, positive; −, negative; PR, progesterone receptor; and ax LN, axillary lymph nodes.†By TNM staging system.‡P= .29.§P= .43.∥P= .98.¶P= .88.For determination of trastuzumab therapy candidates, IM was used on formalin-fixed, paraffin-embedded tissue samples to detect the HER-2/neugene product using an immunohistochemical kit approved by the Food and Drug Administration, Washington, DC (DAKO Hercep Test; DAKO, Carpinteria, Calif). Findings were considered to be positive with scores of 2+ to 3+. Indeterminate samples or samples with a score of 1+ then underwent FISH for further gene characterization (INFORM HER-2/neuGene Detection System; Oncor, Washington, DC). Because of the strong association of oncogene amplification with protein overexpression, the second test (FISH) was used to confirm the indeterminate or weakly positive cases. All samples were carefully scored as either amplifying the oncogene or without amplification (single copy) of the oncogene. Amplification greater than 4 copies by FISH was considered positive, although most of the samples testing positive expressed more than 8 copies.Two databases were compiled based on the 2 different types of testing for determination of HER-2/neustatus. The IM and FISH data sets were analyzed separately; but because of the strong association between the 2 methods,the disease-free interval and recurrence rates were also determined from the combined data.The χ2and logistic regression analyses were performed to compare HER-2/neuamplification with tumor size, ER/PR status, lymph node status, and tumor grade. Overexpression of the gene product was related to disease-free survival period and recurrence using analysis by the Cox regression method and χ2testing, respectively. Further analysis was accomplished comparing increasing number of copies of the HER-2/neugene to decreased disease-free interval to determine if there was a linear relationship. Kaplan-Meier disease-free survival period estimates were plotted from overall recurrence data, as well as distant and local recurrence data. P≤.05 was considered significant.RESULTSSURGERYOf 93 patients, 86 had invasive ductal carcinoma, and 7 had invasive lobular carcinoma. The mean follow-up period for all patients was 56 months. Eighty-eight patients had undergone either modified radical mastectomy or lumpectomy with axillary lymph node dissection. Five patients who had distant metastases (4 to bone, 1 to liver) at presentation never underwent a surgical resection. Only 1 of these 5 was found to amplify the oncogene.ADJUVANT THERAPYSeventy-nine of 93 patients (85%) received adjuvant chemotherapy after surgery. Ten patients were given tamoxifen alone (6 negative for HER-2/neuand 4 positive) and 69 were given systemic chemotherapy (39 negative for HER-2/neuand 30 positive), consisting of either doxorubicin and cyclophosphamide or cyclophosphamide, methotrexate, and 5-fluorouracil. Thirty-eight patients received doxorubicin-based regimens, 22 of whom were negative for HER-2/neu, and 16 of whom were positive. Five patients had inflammatory breast cancer at initial examination (all positive for HER-2/neu) and underwent neoadjuvant therapy prior to resection, which prevented exact tumor size determination. Thirty-eight patients were treated with trastuzumab (Herceptin) at some point during their adjuvant therapy. All displayed 3+ IM except 7: 2 had only 2+ IM, and 5 were tested by FISH alone, all of whom had more than 10 copies of the oncogene. Of 38 patients, 14 (36%) had disease progression while on the drug.SURVIVAL AND ASSOCIATION WITH PROGNOSTIC VARIABLESOf the original 93 patients reviewed, 25 have died. The remaining 68 are still being followed. Twenty-one patients never developed a recurrence after initial therapy. Table 1presents the results of the association of HER-2/neuwith tumor size, receptor status, lymph node metastases, and tumor grade. Thirty subjects (32%) had T1 tumors; 37 (40%), T2; 10 (11%), T3; and 11 (12%), T4. Five (5%) of tumors were measured in the surgical specimen after neoadjuvant therapy and were classified as TX. Of 40 tumors that overexpressed the gene product and/or amplified the HER-2/neuoncogene, 11 (37%) were classified as T1; 17 (46%), T2; 2 (20%), T3; and 9 (82%), T4. Logistic regression analysis of tumor size and amplification reached statistical significance (P= .05). In particular, a T4 tumor had an increased odds ratio of being positive for HER-2/neu(Table 1). A test for trend did not find a statistically significant association of tumor size with HER-2/neustatus (P= .08). This seems to be due to the unexpected small percentage of HER-2/neupositivity at the T3 tumor size, which interrupts the increasing pattern from 1 to 4.All patients were tested for ER/PR status by immunohistochemical analysis. Forty-nine patients (53%) were ER-positive. Nineteen ER-positive patients (39%) had HER-2/neuamplification, as did 20 (50%) of ER-negative patients. Forty-seven (51%) of all patients were PR positive. Nineteen (40%) of PR-positive patients had HER-2/neuamplification, as did 20 (49%) of PR-negative patients. There was no statistical association between ER/PR status and HER-2/neuexpression (P= .29 and P= .43, respectively).A total of 58 (62%) of 93 patients had metastatic disease to the ipsilateral axillary lymph nodes at the time of surgery, without evidence of distant metastatic disease (by computed tomographic scan or magnetic resonance imaging of the brain, chest, and abdomen, and bone scan). HER-2/neuamplification was found in 25 (43%) of 58 lymph node–positive patients and 13 (43%) of 30 lymph node–negative patients (P= .98). The 5 patients treated with neoadjuvant therapy were classified as NX.Seventy-four of the tumors were nuclear grade 2 (intermediate grade) or grade 3 (high grade), while 18 were not graded. HER-2/neuamplification did not vary with grade (G2, 11 [50%] of 22; G3, 25 [48%] of 52; P= .88).HER-2/neuDETERMINATION TECHNIQUESImmunostaining and FISH were both used for determination of the patients' HER-2/neustatus, as previously discussed. However, we sought to determine the prognostic value of each test independently. Using the IM technique alone to assess protein overexpression, the sample size is reduced to 36 patients staining positive and 20 staining negative. To best compare time to relapse, we used survival analysis. A significant difference was not found by the log-rank test (P= .26). The median time to relapse was 27 months in the HER-2/neu–positive group and 38 months in the negative group (Figure 1). The percent relapse in the HER-2/neu–positive group was 78% (28 patients) compared with 88% (18 patients) in the HER-2/neu–negative group. Using Cox regression, the unadjusted risk ratio (RR) estimate of HER-2/neustatus to time to relapse was 1.5 (95% confidence interval [CI], 0.8-2.8).Figure 1.Kaplan-Meier recurrence-free survival curves for immunostaining.Using the FISH data for gene amplification alone, the sample size is reduced to 17 patients in the positive group and 35 in the negative group. To best compare time to relapse, we again used survival analysis. A significant difference was found by the log-rank test (P= .03). The median time to relapse was 29 months in the HER-2/neu–positive group and 41 months in the negative group (Figure 2). The percent relapse in the HER-2/neu–positive group was 63% (11 patients) compared with 70% (25 patients) in the negative group. Using Cox regression, the unadjusted RR estimate of HER-2/neustatus to time to relapse was 2.4 (95% CI, 1.1-5.5).Figure 2.Kaplan-Meier recurrence-free survival curves for fluorescence in situ hybridization.Using both HER-2/neudetermination methods to enhance the accuracy, the average disease-free interval for those patients amplifying the HER-2/neuoncogene was 22 months, whereas, for the patients without amplification or overexpression, it was 40 months (Figure 3). This achieved statistical significance (P= .003) using the log-rank test. Using Cox regression analysis, the HER-2/neustatus remained significantly associated with time to relapse even after adjusting for age and tumor grade (P= .002; adjusted RR, 2.4; 95% CI, 1.4-4.4). Also using Cox regression, the unadjusted RR estimate of HER-2/neustatus to time to relapse was 2.2 (95% CI, 1.3-3.7). Of 72 patients who had disease recurrence, 18 (25%) recurred locally. Results of χ2analysis showed that those patients who had amplification of HER-2/neudid not have a statistically significant increased incidence of local recurrence (50% [20 patients]) compared with patients without amplification (41% [22 patients]) (P= .49). Kaplan-Meier disease-free survival period estimates are shown for local and distant recurrence in Figure 4and Figure 5.Figure 3.Kaplan-Meier recurrence-free survival curves for all patients.Figure 4.Kaplan-Meier recurrence-free survival curves for local recurrence.Figure 5.Kaplan-Meier recurrence-free survival curves for distant recurrence.COMMENTThe method and reproducibility of IM for the HER-2/neugene product has been proven accurate in our laboratory and others,and is a US Food and Drug Administration–approved immunohistochemical assay to determine women likely to respond to treatment with trastuzumab (Herceptin). Prior work has shown that paraffin-embedded archival tissues saved for 2 to 5 years do not suffer from deterioration of antigenicity over time.Fluorescence in situ hybridization has also been proven to be an accurate and reproducible method for assessing HER-2/neugene amplification in human breast cancer.Immunostaining for the HER-2/neugene product and FISH to detect amplification of the oncogene have demonstrated excellent correlation in several studies.Gene amplification detected by FISH is 92% concordant with immunohistochemical detection of overexpression of the oncoprotein.This allows the use of both tests to determine the presence of HER-2/neuin tumors from women with breast cancer.It is interesting to examine the subset analysis detailing the prognostic value of IM alone and HER-2/neustatus. The Kaplan-Meier curves in Figure 1show that those patients who are positive for HER-2/neudo display a worse trend toward earlier recurrence, although this did not reach statistical significance. We attribute this to the small sample size in this subset population. Immunostaining combined with FISH as well as FISH alone both showed a statistically significant decreased disease-free interval and earlier recurrence for patients positive for HER-2/neu.Previous studies have shown that HER-2/neuoverexpression is significantly associated with an increased risk of earlier relapse and death.Other studies have not demonstrated this relationship.There is no consensus in the literature concerning the clinical significance of the amplification of this oncogene. Our study supports the finding of an increased risk of early recurrence (shortened disease-free interval) for the HER-2/neupositive group; however, since most patients in this series were still alive at the conclusion of the study, an increased risk of early death could not be confirmed. In addition, the HER-2/neupositive group's statistically significant overall increased risk of recurrence was independent of tumor size, ER/PR status, and tumor grade. Most local recurrences occurred within the ipsilateral breast after lumpectomy (22% [4 recurrences]), or on the chest wall in proximity to the previous mastectomy scar (67% [12 recurrences]). All patients who underwent lumpectomy had negative findings confirmed in the margins; thus, resection was adequate. Additionally, they received postoperative radiation therapy to the tumor bed. Several other patients had enlarged supraclavicular lymph nodes (distant metastases) at initial examination. Most of these were detected on physical examination by the patient's surgeon at follow-up visits or by subsequent mammography. An increased incidence of recurrence may warrant closer follow-up with surveillance mammography after lumpectomy and frequent clinical examination to detect chest wall nodules.The fact that these HER-2/neu–amplified tumors recur earlier and behave more aggressively has been used by some investigators to propose that high-dose chemotherapy be given to patients positive for HER-2/neuwith uninvolved lymph nodes.Others have disputed this claim.Unfortunately, the present study was too small to assess the significance of node-negative patients who received chemotherapy. Thirty-eight patients in our series were treated with trastuzumab (Herceptin). However, the number of patients was too small to determine any therapeutic benefit of this monoclonal antibody compared with conventional chemotherapy. Despite the use of trastuzumab, which was only given to patients positive for HER-2/neu, their overall disease-free survival period was still significantly shorter. Phase II clinical trials of intravenous trastuzumab therapy have shown an overall response rate of 11.6% with monotherapyand 24.3% in combination with cisplatin.It seems that the current evidence would argue for the need for close follow-up of these patients with clinical examination and mammography to detect recurrence and allow the earliest possible intervention.Prior investigations have also differed on whether there exists a significant association between the HER-2/neustatus and tumor size, tumor grade, and ER/PR status. HER-2/neuamplification has been associated with low ER/PR expression,high tumor grade,and increased metastatic potential.However, most studies have found no statistically significant association between HER-2/neuamplification and tumor size, ER/PR content, and tumor grade.Our study supports the latter findings with the exception of an apparent association between increasing tumor size and gene amplification reaching statistical significance (P= .05). However, this finding could represent a type II statistical error due to sample size, or it may indicate an association. Those patients overexpressing the gene product had a shorter disease-free interval (22 vs 40 months) after an average follow-up of 56 months. However, an increasing number of copies of the oncogene by FISH did not decrease the disease-free interval in a linear fashion. Association was found neither between tumor grade and amplification nor ER/PR status and amplification. Lymph node status was not found to be related to HER-2/neuoverexpression. This is consistent with our previous work which showed that only tumor size predicted the presence of lymph node metastases.This lack of an association between other known prognostic factors and the HER-2/neuoncogene favors its acceptance as an independent predictor of disease recurrence.The HER-2/neuoncogene is an independent prognostic indicator of a subset of breast cancers that are at high risk of recurrence, regardless of tumor size, grade, and lymph node status. Patients amplifying the HER-2/neuoncogene have a shorter disease-free survival period than patients without the oncogene. These results warrant close follow-up with clinical breast and chest wall examination in this group of patients.LCoussensTLYang-FengYCLiaoTyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neuoncogene.Science.1985;230:1132-1139.KSembaNKamataKToyoshimaTYamamotoA v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma.Proc Natl Acad Sci U S A.1985;82:6497-6501.ALSchechterMCHungLVaidyanathanThe neugene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor.Science.1985;229:976-978.SIFukushigeKIMatsubaraMYoshidaLocalization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line.Mol Cell Biol.1986;6:955-958.DJSlamonGMClarkSGWongWJLevinAUllrichWLMcGuireHuman breast cancer: correlation of relapse and survival with amplification of the HER-2/neuoncogene.Science.1987;235:177-182.MFPressLBernsteinPAThomasHER-2/neugene amplification characterized by fluorescence in-situ hybridization: poor prognosis in node-negative breast carcinomas.J Clin Oncol.1997;15:2894-2904.JIsolaTVisakorpiKHolliOKallioniemiAssociation of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients.J Natl Cancer Inst.1992;84:1109-1114.WCWoodDRBudmanAHKorzunDose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma.N Engl J Med.1994;330:1253-1259.HBMussADThorDABerryc-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer.N Engl J Med.1994;330:1260-1266.DJSlamonWGodolphinLAJonesStudies of the HER-2/neuproto-oncogene in human breast and ovarian cancer.Science.1989;244:707-712.DMBarnesGALammieRRMillisAn immunohistochemical evaluation of c-erbB-2 expression in human breast carcinoma.Br J Cancer.1988;58:448-452.GMClarkWLMcGuireFollow-up study of HER-2/neuamplification in primary breast cancer.Cancer Res.1991;51:944-948.AMGerdesONielsenUMohrCorrelation between molecular genetic analyses and immunohistochemical evaluation of the epidermal growth factor receptor and p185HER2.Anticancer Res.1998;18:2529-2534.DLPersonsKABorelliPHHsuQuantification of HER-2/neuand c-myc gene amplification in breast carcinoma using fluorescence in-situ hybridization.Mod Pathol.1997;10:720-727.OPKallioniemiAKallioniemiWKurisuERBB2 amplification in breast cancer analyzed by fluorescence in-situ hybridization.Proc Natl Acad Sci U S A.1992;89:5321-5325.ADThorDABerryDRBudmanerbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer.J Natl Cancer Inst.1998;90:1346-1360.JAlbanellJBellmuntRMolinaMGarciaICaragolBBermejoNode-negative breast cancers with p53(-)/HER-2/neu(-) status may identify women with very good prognosis.Anticancer Res.1996;16:1027-1032.JRMarksPAHumphreyKWuOverexpression of p53 and HER-2/neuproteins as prognostic markers in early stage breast cancer.Ann Surg.1994;219:332-341.MJVan de VijverJLPeterseWJMooiHER-2/neuprotein overexpression in breast cancer.N Engl J Med.1988;319:1239-1241.CWrightBAngusSNicholsonExpression of c-erbB-2 oncoprotein: a prognostic indicator in breast cancer.Cancer Res.1989;49:2087-2090.JMVarleyJESwallowWJBrammerJLWhittakerRAWalkerAlterations to either c-erbB-2 or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis.Oncogene.1987;1:423-425.JDolanBCurranKHenryRLindleyMLeaderc-erbB-2 protein expression and survival in breast carcinoma [abstract].J Pathol.1989;158:354A.MJClineHBattiforaJYokotaProto-oncogene abnormalities in human breast cancer: correlation with anatomic features and clinical course of the disease.J Clin Oncol.1987;5:999-1006.BAGustersonLGMachinWJGullickc-erbB-2 expression in benign and malignant breast disease.Br J Cancer.1988;58:453-455.IUAliGCampbellRLidereauRCallahanLack of evidence for the prognostic significance of c-erbB-2 amplification in human breast carcinoma.Oncogene Res.1988;3:139-142.DMBarnesGALammieRRMillisWJGullickDSAllenDGAltmanAn immunohistochemical evaluation of c-erbB-2 expression in human breast carcinoma.Br J Cancer.1988;58:448-451.WJGullickSBLoveCWrightc-erbB-2 Protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes.Br J Cancer.1991;63:434-438.JBaselgaDTripathyJMendelsohnPhase II study of weekly intravenous trastuzumab in patients with HER-2/neu-overexpressing metastatic breast cancer.Semin Oncol.1999;26:78-83.MDPegramDJSlamonCombination therapy with trastuzumab and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity.Semin Oncol.1999;26:89-95.OPKallioniemiKHolliTVisakorpiAssociation of c-erbB-2 oncogene overexpression with high rate of cell proliferation, increased risk for visceral metastases and poor long-term survival in breast cancer.Int J Cancer.1991;49:650-655.AKTandonGMClarkGCChamnessHER-2/neuoncogene protein and prognosis in breast cancer.J Clin Oncol.1989;7:1120-1128.SPaikRHazanERFisherPathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erb B-2 protein overexpression in primary breast cancer.J Clin Oncol.1990;8:103-112.MCPatersonKDDietrichJDanylukCorrelation between c-erbB-2 amplification and risk of early relapse in node-negative breast cancer.Cancer Res.1991;51:556-567.AScorilasJYotisKStravolemosc-erbB-2 overexpression may be used an independent prognostic factor for breast cancer patients.Anticancer Res.1995;15:1543-1548.FDescotesJJPavyGLAdessiHuman breast cancer: correlation study between HER-2/neuamplification and prognostic factors in an unselected population.Anticancer Res.1993;13:119-124.VVelanovichWSzymanskiLymph node metastasis in breast cancer: common prognostic markers lack predictive value.Ann Surg Oncol.1998;5:613-619.Presented at the 47th Annual Meeting of the Michigan Chapter of the American College of Surgeons, Acme, Mich, May 4-6, 2000.Corresponding author and reprints: John Alfred Carr, MD, Department of General Surgery K-8, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689.
TI - The Association of HER-2/neuAmplification With Breast Cancer Recurrence
JF - JAMA Surgery
DO - 10.1001/archsurg.135.12.1469
DA - 2000-12-01
UR - https://www.deepdyve.com/lp/american-medical-association/the-association-of-her-2-neuamplification-with-breast-cancer-NVH6CIxKXv
SP - 1469
EP - 1474
VL - 135
IS - 12
DP - DeepDyve
ER -