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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3126-3132 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.11.154
Her-2/neu Overexpression and Amplification in Uterine Papillary Serous CarcinomaFrom the Departments of Gynecologic Oncology, Pathology, and Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Karen H. Lu, MD, Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 440, Houston, TX 77030-4009; e-mail: khlu{at}mdanderson.org
PURPOSE: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer characterized by early metastasis, resistance to therapy, and a high mortality rate. Little is known about the biology of these tumors. Smaller studies suggest that Her-2/neu may be involved in the tumorigenesis of this disease. The purpose of this study was to evaluate the protein expression and gene amplification of Her-2/neu in UPSC and to determine its prognostic value. PATIENTS AND METHODS: Tumor tissue from 68 patients with UPSC treated at The University of Texas M.D. Anderson Cancer Center from 1989 to 2002 was available. Her-2/neu expression was evaluated by immunohistochemistry (IHC). Overexpression was defined as complete membrane staining in greater than 10% of the cells. In tumors with overexpression of Her-2/neu by IHC, fluorescence in situ hybridization (FISH) was performed to assess gene amplification. Clinical and pathologic information was obtained from medical records.
RESULTS: Twelve (18%) of 68 tumors demonstrated Her-2/neu overexpression. Of these, only two showed gene amplification. When evaluating all 68 patients, Her-2/neu overexpression was associated with a poorer overall survival (OS; P = .008). In our multivariate Cox proportional hazards models, Her-2/neu IHC overexpression, lymph node status, and stage were each associated with OS (P CONCLUSION: Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.
First described by Hendrickson et al1 in 1982, uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial carcinoma. Although less than 10% of endometrial cancers are UPSC, they account for over 50% of recurrences and deaths caused by endometrial cancer. The 5-year overall survival (OS) rate for women with UPSC is 46%.2 In contrast, women with endometrioid endometrial cancer have an 80% to 85% 5-year OS rate. UPSC will often have metastases to regional lymph nodes and the omentum, even in the presence of minimal uterine disease.2 Therefore, comprehensive surgical staging is recommended for all patients with UPSC, regardless of the depth of myometrial invasion of the tumor.2-5 The median OS time is 91.9 months for patients with stage I or II disease and 28.8 months for patients with stage III or IV disease.2 Chemotherapy is recommended for stage III and IV disease, as well as recurrent disease. Responses to platinum-based regimens and single-agent paclitaxel have been observed.6-8 However, UPSC is relatively chemoresistant from its onset, with low response rates and a short duration of response.6-8 Most studies on UPSC are limited by small patient numbers. To date, little is known about the biology of these tumors. Mutations in p53 are found in greater than 90% of UPSCs.9,10 Aneuploidy has also been identified in a number of these tumors.11,12 No prognostic markers have been identified. The human Her-2/neu gene product, also called p185HER2 or c-erbB2, is a member of the epidermal growth factor receptor transmembrane receptor tyrosine kinase family.13,14 Overexpression of Her-2/neu has been found to play a role in cellular transformation, tumorigenesis, and metastasis.15,16 In breast cancers, 25% to 30% of tumors overexpress Her-2/neu.17-19 Overexpression of Her-2/neu is considered a negative prognostic factor for women with breast cancer and is associated with a shorter disease-free interval and worse OS.17,20-22 In ovarian cancer, early data reported over 30% overexpression of Her-2/neu.23 Most recently, prospective results from a Gynecologic Oncology Group study found that a significantly lower percentage of recurrent or persistent ovarian cancers (11.4%, or 95 of 837 cancers) overexpressed Her-2/neu by immunohistochemistry (IHC).24 In patients with ovarian cancer, Her-2/neu overexpression has been associated with a decreased median survival,23 but this has not been a consistent finding.25 The US Food and Drug Administration has approved both fluorescence in situ hybridization (FISH) and IHC as clinical tests for breast cancer. However, there is not complete concordance between gene amplification and protein overexpression.18,26-29 Smaller studies have suggested that Her-2/neu overexpression may be present in a disproportionate number of endometrial cancers and UPSC tumors in particular.30-32 The purpose of this study was to evaluate Her-2/neu expression by IHC in a large series of UPSCs. In addition, we wanted to determine whether Her-2/neu protein overexpression correlated with gene amplification. Finally, we wanted to determine the potential prognostic value of Her-2/neu overexpression in UPSCs.
Clinical and Pathologic Information After institutional review board approval, we reviewed 129 patients with UPSC who were surgically treated at the University of Texas M.D. Anderson Cancer Center since 1989.2 From this group, 68 uterine specimens were available for analysis. Clinical records and surgical pathology reports were reviewed. Demographic and clinical information, including age at the time of diagnosis, race, weight, smoking history, other cancer history, family history, history of diabetes, and parity, was obtained from medical records. Treatment and follow-up information was also obtained from the medical records. Patients received a variety of adjuvant therapies or were observed without therapy. When information on survival was not in the medical record, death certificate information was obtained. If this information was not available, the patient was censored after her last contact. OS was the primary clinical end point evaluated. OS was calculated from the date of the surgical diagnosis. All patients underwent exploratory surgery, hysterectomy, bilateral salpingo-oophorectomy, and pelvic cytologic evaluations. Stage assignment was made according to the International Federation of Gynecology and Obstetrics (FIGO) surgical staging of endometrial cancer criteria set forth in 1988. All pathologic diagnoses were made by gynecologic pathologists at the M.D. Anderson Cancer Center. Pathologic criteria evaluated included lymph vascular space invasion, depth of myometrial invasion, and lymph node status. Because studies have shown that the clinical course of mixed tumors with serous components is not different than pure UPSC tumors,2,33 patients with tumors that had mixed histologic subtypes (including a serous component) were included in this study. The histologic tumor type (ie, pure UPSC or mixed carcinoma involving serous and other cell types) was determined on the basis of uterine pathology. For example, if the endometrium had mixed serous and endometrioid components but the extrauterine disease was serous carcinoma, the tumor was classified as a mixed histologic tumor.
IHC IHC staining was performed on 5-µm-thick paraffin-embedded sections using the streptavidin-biotin 2 system (Dako, Carpinteria, CA), according to the manufacturer's instructions. The sections were examined by light microscopy by two different pathologists (a gynecologic pathologist, R.R.B., and a breast pathologist/cytopathologist, N.S.). IHC evaluation was performed without knowledge of the clinical outcome. The intensity of immunostaining was graded as follows: negative (0); incomplete membranous staining or complete membranous staining in less than 10% of the tumor cells (+1); moderate intensity, complete membranous staining in greater than 10% of the tumor cells (+2); or strong intensity, complete membranous staining in greater than 10% of the tumor cells (+3). Tumors with 2+ or 3+ staining were considered positive for antibody overexpression. FISH analysis was performed in all positive (2+ or 3+) cases. If there was a discrepancy between the two pathologists' interpretation of the immunostaining (ie, same specimen positive by one pathologist and negative by the other pathologist), the tumor was considered positive for overexpression. These cases were included in the FISH analysis for gene amplification to ensure no potentially positive cases were missed.
FISH
Statistical Considerations
IHC and FISH Analysis Twelve (18%) of 68 patients overexpressed Her-2/neu by IHC. One pathologist found 11 (16%) of 68 tumors positive for Her-2/neu. The second pathologist found 10 (15%) of 68 tumors positive. There was a difference in interpretation in three of the specimens. There was an excellent measure of agreement between the two pathologists (  = 0.83, SE = 0.095). Of the 12 tumors that were determined to overexpress Her-2/neu by at least one of the pathologists, two had 3+ staining. The remaining 10 tumors demonstrated 2+ immunostaining. The 12 tumors that demonstrated 2+ or 3+ staining were evaluated by FISH for amplification of the specific Her-2/neu gene. Two (17%) of 12 demonstrated specific gene amplification. One of these tumors had 3+ IHC expression of Her-2/neu. The other had 2+ expression. Eight (75%) of 12 tumors demonstrated aneuploidy of chromosome 17. Both tumors that had amplification of Her-2/neu were also aneuploid (ie, increased copies of both Her-2/neu and CEP 17 and a ratio greater than 2.0).
Clinicopathologic Information
See Table 2 for pathologic information. There were no significant differences between the Her-2/neu–positive and –negative tumors with regard to pathologic characteristics. Twelve patients did not have a lymph node sampling performed. Nine of these 12 patients had high-stage disease.
In addition, there were no distinguishing clinical or pathologic characteristics in the two patients who had gene amplification of Her-2/neu. Neither had a personal or family history of breast cancer.
Prognosis Kaplan-Meier estimation of OS between Her-2/neu–positive and –negative tumors is shown in Figure 1. For the patients with Her-2/neu–positive tumors, the median OS was 18 months (range, 6 to 56 months) compared with 48 months (range, < 1 to 162 months) for the Her-2/neu–negative tumors (5-year OS, 0% v 45%, respectively; P = .005). There were no treatment differences that might explain survival differences between the two groups.
By univariate analyses, Her-2/neu IHC overexpression (P = .008), lymph vascular space invasion (P = .049), lymph node status (positive or unknown, P < .001), and high stage (P = .003) were significantly associated with a shorter OS; depth of myometrial invasion was not (Table 3). Most of the patients with unknown lymph node status had high-stage disease (nine of 12 patients), and the other three patients with unknown lymph node status and low-stage disease died. In the subgroup of 42 women with high-stage (stages III or IV) disease, the median OS was 17 months for patients with Her-2/neu–positive tumors (n = 10) and 39 months for patients with Her-2/neu–negative tumors (n = 32, P = .03).
The four variables used in the multivariate analysis were Her-2/neu IHC overexpression, lymph vascular space invasion, lymph node status, and stage. Lymph node status (positive or unknown) and Her-2/neu IHC overexpression were the only factors associated with shorter OS (P  .05). Because unknown lymph node status may act as a surrogate for high-stage disease, we also evaluated a multivariate proportional hazards model without lymph node status. In this model, high-stage disease and Her-2/neu IHC overexpression were the only factors associated with shorter OS.
Prognostic and therapeutic implications of Her-2/neu overexpression and amplification in solid tumors continue to evolve. In this study, we found that there is an 18% incidence of Her-2/neu overexpression in a large series of UPSC. Gene amplification of Her-2/neu was rare. In addition, we demonstrated that Her-2/neu IHC overexpression is a prognostic marker for this disease. This study demonstrated a lower rate of Her-2/neu protein overexpression in UPSCs when compared with other studies. Most recently, Santin et al34 found that 80% of UPSCs (eight of 10 UPSCs) overexpress Her-2/neu. Prat et al30 evaluated 10 cases of UPSC and found protein overexpression in 40% of the tumors. In a study of 95 endometrial carcinomas, Berchuck et al32 found that three (25%) of 12 UPSC tumors had high expression of Her-2/neu. All of these studies are hindered by a small sample size. Other studies do not differentiate UPSC from other types of endometrial cancer. Khalifa et al35 reported that 14 (58%) of 24 of papillary serous and clear-cell carcinomas overexpressed Her-2/neu. Coronado et al36 reported that six (22%) of 27 nonendometrioid tumors (including papillary serous, clear cell, and adenosquamous) overexpressed Her-2/neu. Hetzel et al37 reported that 27% of nonendometrioid tumors (nine of 33 tumors) overexpress Her-2/neu.
Differences in the rate of positivity of overexpression of Her-2/neu can also be explained by the inherent variability in IHC. Protein targets may differ among the IHC methods used. The monoclonal antibodies used in this study target the 3b5 and e2-4001 domain of the Her-2/neu protein. Both of these have been found to be reliable antibodies for detecting c-erbB-2 protein overproduction in routinely processed tissue.38,39 The criteria for Her-2/neu positivity requires complete membranous staining in greater than 10% of the tumor cells. In the previous studies, this criteria was not clearly defined.30,32,34-37 Two of the studies required membranous staining35,36 without distinguishing complete from partial membranous staining; the scoring systems used in the other studies were based solely on the intensity of staining.30,32,34,37 Partial or incomplete membranous staining likely accounts for the higher rates of Her-2/neu positivity reported in the earlier studies. Finally, interobserver variability has been demonstrated in studies with multiple pathologists interpreting the results of IHC.39-41 For our study, two pathologists independently reviewed cases. Both pathologists were blinded to the stage of disease and clinical information. There was an excellent measure of agreement between scores ( FISH directly measures the number of DNA gene copies rather than expression of the protein product. In breast cancer, gene amplification is present in approximately 25% of all cases.42-44 There is a concordance between IHC scores of 0 and 1+ and the absence of gene amplification, as well as concordance between an IHC score of 3+ and the presence of gene amplification. However, in breast cancer, the association between an IHC score of 2+ and FISH positivity is not as strong. For this study, we tested all of the tumors that were considered 2+ or 3+ by IHC. Of the 12 tumors tested by FISH, only two demonstrated gene amplification of Her-2/neu. The etiology of protein overexpression in the absence of gene amplification has not been explained in UPSC. In breast cancer specimens, overexpression has been observed in specimens in the absence of amplification.18,27,28 A possible explanation for the discordance between protein overexpression and genetic amplification is genetic aneuploidy. Of the 12 cases in which we performed FISH, 67% (eight of 12 cases) demonstrated aneuploidy. In breast cancer, Lebeau et al42 found chromosome 17 polysomy in cases that were IHC positive but that did not have gene amplification. The reported frequency of chromosome 17 aneuploidy in breast cancer is up to 21%.45 In addition, low-level amplification (ie, three or four copies of Her-2/neu signals per nucleus in the absence of the required 2:1 ratio of Her-2/neu to chromosome 17 signal) may cause the protein overexpression.46 We found that Her-2/neu overexpression along with lymph node status (or stage) were the only factors associated with a shorter OS when compared with other traditional clinical and pathologic features. The failure to establish significance for depth of myometrial invasion and lymph vascular space invasion in the multivariate analyses could be partially explained by the small sample size and imprecision of the analysis. Although the model does suggest that, after adjusting for some standard covariates, Her-2/neu overexpression remains significant, the results by themselves should not be considered definitive. No other studies have examined Her-2/neu overexpression as a predictor of OS in women with UPSC. Coronado et al36 examined different histologic subtypes of endometrial cancer and reported that Her-2/neu expression was more frequent in tumors with advanced-stage disease, nonendometrioid subtypes, deep myometrial invasion, and high-grade histology. The authors did not find Her-2/neu to be an independent prognostic factor. In 100 cases of all histologic subtypes of endometrial cancer, Lukes et al47 found that Her-2/neu overexpression was a predictor of recurrent or persistent disease. Berchuck et al32 concluded that Her-2/neu expression in all types of endometrial cancer was associated with an increased incidence of death from persistent or recurrent disease. In this study, we found an association between a personal history of breast cancer and UPSC tumors that overexpress Her-2/neu. Unfortunately, we do not have the Her-2/neu status of the breast tumors for these patients. Numerous studies have found a relationship of UPSC developing in patients with a personal history of breast cancer.2,3,48 Thus far, this relationship has not been described on a molecular or genetic level.49 The implications of such an association are unknown. In breast cancer, trastuzumab (Herceptin; Genentech, South San Francisco, CA), a monoclonal antibody directed against Her-2/neu, is widely used for its approved indication as a treatment for advanced or recurrent breast cancer in patients whose tumors demonstrate overexpression of Her-2/neu. Response rates to single-agent therapy with this antibody have ranged from 12% to 27%.50-52 Recently, better response rates have been shown in the subset of women whose breast tumors demonstrate 3+ Her-2/neu overexpression by IHC or 2+ Her-2/neu overexpression with gene amplification by FISH.52,53 Specifically, in tumors with moderate expression (2+) of Her-2/neu by IHC, response to trastuzumab was greater in the setting of specific gene amplification (34% v 7% for those tumors without specific gene amplification).52 In the Gynecologic Oncology Group study of trastuzumab for the treatment of recurrent ovarian cancer, criteria for inclusion included 2+ or 3+ overexpression by IHC. They found a 7% (three of 41 patients) overall response rate (one complete response and two partial responses) and a 39% stable disease rate.24 The authors concluded that trastuzumab therapy for recurrent ovarian cancer is limited by the low frequency of Her-2 overexpression and the low rate of response rates in patients with Her-2 overexpression. FISH testing was not performed in this study. It is unclear whether limiting the inclusion criteria to 3+ overexpression by IHC or 2+ overexpression with gene amplification would have resulted in a more favorable outcome. In conclusion, positive IHC expression of Her-2/neu was seen in 18% of UPSCs. Her-2/neu overexpression was rarely associated with gene amplification. Positive IHC expression was associated with more aggressive disease and a worse overall prognosis. Despite the low rate of overexpression and gene amplification, the value of trastuzumab therapy in patients with Her-2/neu–expressing UPSC is unknown and should be further evaluated in a clinical trial setting.
The authors indicated no potential conflicts of interest.
Presented at the 35th Annual Meeting of the Society of Gynecologic Oncology, San Diego, CA, February 8, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Hendrickson M, Ross J, Eifel P, et al: Uterine papillary serous carcinoma: A highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 6:93-108, 1982[Medline] 2. Slomovitz BM, Burke TW, Eifel PJ, et al: Uterine papillary serous carcinoma (UPSC): A single institution review of 129 cases. Gynecol Oncol 91:463-469, 2003[CrossRef][Medline] 3. Goff BA, Kato D, Schmidt RA, et al: Uterine papillary serous carcinoma: Patterns of metastatic spread. Gynecol Oncol 54:264-268, 1994[CrossRef][Medline] 4. Chan JK, Loizzi V, Youssef M, et al: Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium. Gynecol Oncol 90:181-185, 2003[CrossRef][Medline] 5. Geisler JP, Geisler HE, Melton ME, et al: What staging surgery should be performed on patients with uterine papillary serous carcinoma? Gynecol Oncol 74:465-467, 1999[CrossRef][Medline]
6. Hoskins PJ, Swenerton KD, Pike JA, et al: Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: A phase II study. J Clin Oncol 19:4048-4053, 2001 7. Ramondetta L, Burke TW, Levenback C, et al: Treatment of uterine papillary serous carcinoma with paclitaxel. Gynecol Oncol 82:156-161, 2001[CrossRef][Medline] 8. Zanotti KM, Belinson JL, Kennedy AW, et al: The use of paclitaxel and platinum-based chemotherapy in uterine papillary serous carcinoma. Gynecol Oncol 74:272-277, 1999[CrossRef][Medline] 9. Lax SF, Kendall B, Tashiro H, et al: The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: Evidence of distinct molecular genetic pathways. Cancer 88:814-824, 2000[CrossRef][Medline] 10. Tashiro H, Isacson C, Levine R, et al: p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol 150:177-185, 1997[Abstract] 11. Kato DT, Ferry JA, Goodman A, et al: Uterine papillary serous carcinoma (UPSC): A clinicopathologic study of 30 cases. Gynecol Oncol 59:384-389, 1995[CrossRef][Medline] 12. Newbury R, Schuerch C, Goodspeed N, et al: DNA content as a prognostic factor in endometrial carcinoma. Obstet Gynecol 76:251-257, 1990[Medline]
13. Akiyama T, Sudo C, Ogawara H, et al: The product of the human c-erbB-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity. Science 232:1644-1646, 1986
14. Coussens L, Yang-Feng TL, Liao YC, et al: Tyrosine kinase receptor with extensive homology to EGC receptor shares chromosomal location with neu oncogene. Science 230:1132-1139, 1985 15. Chazin VR, Kaledo M, Miller AD, et al: Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene 7:1859-1866, 1992[Medline]
16. DiFiore PP, Pierce JH, Kraus MH, et al: ErbB-2 is a potent oncogene when overexpressed in NIH-3T3 cells. Science 237:178-182, 1987
17. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of HER-2/neu oncogene. Science 235:177-182, 1987
18. Slamon DJ, Godolphin W, Jones LA, et al: Studies of HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989
19. Berger MS, Locher GW, Saurer S, et al: Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res 48:1238-1243, 1988 20. Gusterson BA, Gelber RD, Goldhirsch A, et al: Prognostic importance of c-erbB-2 expression in breast cancer. J Clin Oncol 10:1049-1056, 1992[Abstract]
21. Andrulis IL, Bull SB, Blackstein ME, et al: Neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. J Clin Oncol 16:1340-1349, 1998 22. Ravdin PM, Chamness GC: The c-erbB-2 protooncogene as a prognostic and predictive marker in breast cancer: A paradigm for the development of other macromolecular markers—A review. Gene 159:19-27, 1995[CrossRef][Medline]
23. Berchuck A, Kamel A, Whitaker R, et al: Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50:4087-4091, 1990
24. Bookman MA, Darcy KM, Clarke-Pearson D, et al: Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: A phase II trial of the Gynecologic Oncology Group. J Clin Oncol 21:283-290, 2003 25. Rubin SC, Finstad CL, Wong GY, et al: Prognostic significance of HER-2/neu expression in advanced epithelial ovarian cancer: A multivariate analysis. Am J Obstet Gynecol 168:162-169, 1993[Medline]
26. Jacobs TW, Gown AM, Yaziji H, et al: Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol 17:1974-1982, 1999 27. Persons DL, Borelli KA, Hsu PH: Quantitation of HER-2/neu and c-myc gene amplification in breast carcinoma using fluorescence in situ hybridization. Mod Pathol 10:720-727, 1997[Medline] 28. Pauletti G, Godolphin W, Press MF, et al: Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescent in situ hybridization. Oncogene 13:63-72, 1996[Medline]
29. Szollosi J, Balazs M, Feuerstein BG, et al: ERBB-2 (HER2/neu) gene copy number, p185HER-2 overexpression, and intratumor heterogeneity in human breast cancer. Cancer Res 55:5400-5407, 1995 30. Prat J, Oliva E, Lerma E, et al: Uterine papillary serous adenocarcinoma: A 10-case study of p53 and c-erbB-2 expression and DNA content. Cancer 74:1778-1783, 1994[CrossRef][Medline] 31. Rolitsky CD, Theil KS, McGaughy VR, et al: HER-2/neu amplification and overexpression in endometrial carcinoma. Int J Gynecol Pathol 18:138-143, 1999[Medline] 32. Berchuck A, Rodriguez G, Kinney RB, et al: Overexpression of HER-2/neu in endometrial cancer is associated with advanced stage disease. Am J Obstet Gynecol 164:15-21, 1991[Medline] 33. Carcangiu ML, Chambers JT: Uterine papillary serous carcinoma: A study on 108 cases with emphasis on the prognostic significance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma. Gynecol Oncol 47:298-305, 1992[CrossRef][Medline]
34. Santin AD, Bellone S, Gokden M, et al: Overexpression of HER-2/neu in uterine papillary serous carcinoma. Clin Cancer Res 8:1271-1279, 2002 35. Khalifa MA, Mannel RS, Haraway SD, et al: Expression of EGFR, HER-2/neu, p53, and PCNA in endometrioid, serous papillary, and clear cell endometrial adenocarcinomas. Gynecol Oncol 53:84-92, 1994[CrossRef][Medline] 36. Coronado PJ, Vidart JA, Lopez-Asenjo JA, et al: p53 overexpression predicts endometrial carcinoma recurrence better than HER-2/neu overexpression. Eur J Obstet Gynecol Reprod Biol 98:103-108, 2001[CrossRef][Medline] 37. Hetzel DJ, Wilson TO, Keeney GL, et al: HER-2/neu expression: A major prognostic factor in endometrial cancer. Gynecol Oncol 47:179-185, 1992[CrossRef][Medline] 38. Singleton TP, Niehans GA, Gu F, et al: Detection of c-erbB-2 activation in paraffin-embedded tissue by immunohistochemistry. Hum Pathol 23:1141-1150, 1992[CrossRef][Medline]
39. Hoang MP, Sahin AA, Ordonez NG, et al: HER-2/neu gene amplification compared with HER-2/neu protein overexpression and interobserver reproducibility in invasive breast carcinoma. Am J Clin Pathol 113:852-859, 2000
40. Press MF, Hung G, Godolphin W, et al: Sensitivity of HER-2/neu antibodies in archival tissue samples: Potential source of error in immunohistochemical studies of oncogene expression. Cancer Res 54:2771-2777, 1994 41. Bilous M, Dowsett M, Hanna W, et al: Current perspectives on HER2 testing: A review of national testing guidelines. Mod Pathol 16:173-182, 2003[CrossRef][Medline]
42. Lebeau A, Deimling D, Kaltz C, et al: HER-2/neu analysis in archival tissue samples of human breast cancer: Comparison of immunohistochemistry and fluorescence in situ hybridization. J Clin Oncol 19:354-363, 2001 43. Ross JS, Fletcher JA: HER-2/neu (c-erb-B2) gene and protein in breast cancer. Am J Clin Pathol 112:S53-S67, 1999 (suppl 1)[Medline] 44. Revillion F, Bonneterre J, Peyrat JP: ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 34:791-808, 1998 45. Jimenez RE, Wallis T, Tabasczka P, et al: Determination of HER-2/neu status in breast carcinoma: Comparative analysis of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol 13:37-45, 2000[CrossRef][Medline] 46. Xing WR, Gilchrist KW, Harris CP, et al: FISH detection of HER-2/neu oncogene amplification in early onset breast cancer. Breast Cancer Res Treat 39:203-212, 1996[CrossRef][Medline] 47. Lukes AS, Kohler MF, Pieper CF, et al: Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer. Cancer 73:2380-2385, 1994[CrossRef][Medline] 48. Grice J, Ek M, Greer B, et al: Uterine papillary serous carcinoma: Evaluation of long-term survival in surgically staged patients. Gynecol Oncol 69:69-73, 1998[CrossRef][Medline] 49. Goshen R, Chu W, Elit L, et al: Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome. Gynecol Oncol 79:477-481, 2000[CrossRef][Medline]
50. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999
51. Baselga J, Tripathy D, Mendelsohn J, et al: Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737-744, 1996
52. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002 53. Mass R, Sanders C, Kasian C, et al: The concordance between the clinical trials assay (CTA) and fluorescence in situ hybridization (FISH) in the Herceptin pivotal trials. Proc Am Soc Clin Oncol 19:75a, 2000 (abstr 291) Submitted November 26, 2003; accepted April 29, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests were performed. Cohen's 
