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© 2000 American Society for Clinical Oncology Overexpression of Her-2 in Patients With Poorly Differentiated Carcinoma or Poorly Differentiated Adenocarcinoma of Unknown Primary SiteFrom the Sarah Cannon Cancer Center, Nashville, TN. Address reprint requests to John D. Hainsworth, MD, 250 25th Ave, North, Suite 412, Nashville, TN 37203.
PURPOSE: To determine the frequency of Her-2 overexpression in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. PATIENTS AND METHODS: Tumor specimens from 100 patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma were stained for the Her-2 protein using the Dako immunohistochemical method. Clinical and pathologic characteristics of patients with and without Her-2 overexpression were compared. RESULTS: Staining for Her-2 overexpression was successful in 94 of 100 patients. Ten (11%) of 94 tumor specimens overexpressed Her-2. Eight of 10 overexpressors had poorly differentiated adenocarcinoma, and all overexpressors had predominant tumor location above the diaphragm, usually in the mediastinum or lungs. CONCLUSION: Her-2 overexpression occurs in a minority of patients with poorly differentiated carcinoma/adenocarcinoma of unknown primary site. Because most overexpressors had poorly differentiated adenocarcinoma, further evaluation of patients with adenocarcinoma of unknown primary site is necessary to determine the frequency of Her-2 overexpression in this common subgroup. Evaluation of the efficacy of trastuzumab in Her-2 overexpressors with carcinoma of unknown primary site is indicated.
THE HUMAN HER2/neu oncogene encodes a transmembrane glycoprotein that shares sequence homology with epidermal growth factor receptor.1 Overexpression of this oncogene has been documented in 15% to 30% of human breast cancer, and this overexpression has been correlated with poor clinical outcome.2-5 Overexpression of Her-2 has also been reported in carcinomas from several other primary tumor sites, including lung, ovary, and colon.2,6,7 With the introduction of the humanized anti-Her-2 antibody trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), overexpression of Her-2 has potential therapeutic as well as prognostic implications. In patients with advanced breast cancer, treatment with humanized anti-Her-2 antibody has produced remissions as a single agent8 and has increased response rate and survival when used concurrently with chemotherapy.9 Patients with carcinoma of unknown primary site are a heterogeneous group with respect to histopathologic characateristics, clinical characteristics, and biologic nature of the tumor. Overexpression of the Her-2 protein in patients with carcinoma of unknown primary site has not been previously investigated. However, there are several reasons to suspect that a number of these tumors may overexpress Her-2. First, Her-2 overexpression has been observed in a variety of adenocarcinomas, the most common histologic diagnosis in patients with carcinoma of unknown primary site. Second, many patients with carcinoma of unknown primary site have tumors that are poorly differentiated, aggressive, and possessed of a high metastatic potential. This phenotype has been associated with Her-2 overexpression in patients with breast cancer. Finally, autopsy examinations in patients with carcinoma of unknown primary site have documented occult primary tumors in locations known to be associated with Her-2 overexpression (eg, lung, pancreas, colon, and breast).10 For these reasons, we retrospectively obtained tumor specimens from 100 patients with either poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site to determine the frequency of Her-2 overexpression in this patient population. The tumor specimens studied were from patients who had received uniform treatment with cisplatin-based chemotherapy and have been previously reported.11 In this brief article, we report the results of immunoperoxidase staining for Her-2 overexpression in this large group of patients and correlate these results with clinical course and response to treatment.
Paraffinized tissue blocks from 100 patients treated between 1980 and 1988 were obtained and sectioned. All tumor specimens included in this series were obtained by either surgical or core-needle biopsy; fine-needle aspiration specimens were excluded. Immunoperoxidase staining for the Her-2 protein was performed using an automated stainer (Dako, Carpentaria, CA), and the polyclonal Her-2 antibody Non-HercepTest (Dako) was used in conjunction with 20 minutes of antigen retrieval (60°C) in a steam bath. All slides were reviewed by the same pathologist (W.J.L.). Her-2 staining was quantified using the following scale: 0, no membrane staining; 1+, barely perceptible light membranous rimming that may not totally encircle the cell membrane; 2+, light to moderate membranous rimming that totally encircles the membrane; and 3+, moderate to strong membrane rimming that totally encircles the membrane. Tumors were considered to overexpress Her-2 if membrane staining of 2+ or 3+ intensity was present. Staining for Her-2 was technically successful in 94 specimens. In six cases, insufficient tumor was included in the biopsy specimen for successful interpretation. Table 1 lists the clinical and pathologic characteristics of the 94 patients with successful immunoperoxidase staining for Her-2. The median age was relatively young, and males outnumbered females 3:1. Pathologic diagnoses included poorly differentiated carcinoma (51 patients; 54%), poorly differentiated adenocarcinoma (36 patients; 38%), poorly differentiated neuroendocrine carcinoma (six patients; 6%), and poorly differentiated squamous carcinoma (one patient; 1%). Seventy-six (81%) of 94 patients had metastases in two or more sites. Eighty-nine patients (95%) received chemotherapy with cisplatin-based combination regimens considered standard for treatment of germ cell tumors (ie, cisplatin/vinblastine/bleomycin, cisplatin/etoposide/bleomycin, or variants).12,13
Her-2 overexpression was found in 10 (11%) of 94 tumor specimens. Her-2 staining was graded as 2+ in seven patients and as 3+ in three patients. In the 10 patients who overexpressed Her-2, cells with distinct cytoplasmic membrane staining for Her-2 ranged from 25% to 100%. Table 1 compares clinical and treatment-related features of patients who had positive Her-2 staining. Eight (80%) of 10 Her-2 overexpressors were male, similar to the percentage of males in the overall group. Neither of the two female overexpressors had clinical features suggesting metastatic breast cancer. Eight (80%) of 10 overexpressors had poorly differentiated adenocarcinoma, which was higher than the 38% with this diagnosis in the entire group of patients. All 10 Her-2 overexpressors had dominant tumor locations above the diaphragm, either in the mediastinum, lungs, or multiple supradiaphragmatic sites. No major differences in overall response rate to chemotherapy were observed, although the complete response rate was somewhat lower in the group of Her-2 overexpressors (20% v 39%). However, the relatively small number of overexpressors makes definitive comparisons impossible.
Patients with carcinoma of unknown primary site are a diverse group, with variable clinical features, histopathologic characteristics, biologic characteristics of tumor, and response to therapy. Adenocarcinoma and poorly differentiated adenocarcinoma are seen most commonly in this group and account for 60% to 70% of all carcinomas of unknown primary site.14 Within this large group, several subsets with specific treatment recommendations can be recognized on the basis of clinical and/or pathologic features. Examples of these subsets include women with axillary node metastases, women with adenocarcinoma involving the peritoneum, and young men with clinical features of extragonadal germ cell tumor.15-17 However, most patients with carcinoma of unknown primary site do not fit any defined treatable subset, and determining effective treatment for these patients has been difficult. Until recently, empiric therapy with a variety of traditional fluorouracil, doxorubicin, or cisplatin-based regimens produced response rates of only 20% to 30% and had no definite effects on the 5- to 8-month median survival.18-20 Recently, results of a phase II trial with an empiric regimen containing paclitaxel, carboplatin, and etoposide yielded a 47% response rate and a 13-month median survival in a group of 55 patients.21 Confirmation of this improved treatment result with paclitaxel-based therapy and further investigation of other new antineoplastic agents (eg, gemcitabine, topoisomerase I inhibitors, vinorelbine) are still to come. The introduction of trastuzumab, a humanized anti-Her-2 antibody, has provided an additional treatment option for patients with metastatic breast cancer who overexpress the Her-2 protein.8,9 Although some patients with a variety of other primary tumors are known to overexpress Her-2, the efficacy of the trastuzumab monoclonal antibody is unknown. In designing this retrospective study, we hoped to document a subset of patients with carcinoma of unknown primary site who overexpressed Her-2 and therefore may be candidates for an additional type of treatment. The tumors studied in this retrospective trial were selected from our tissue bank of patients with carcinoma of unknown primary site treated during the last 15 years. Tumors included in this series were from patients who were treated with cisplatin-based chemotherapy as part of a large, previously reported series.11 Patients in this particular trial were not representative of the general population of unknown primary cancer patients; instead, they were selected on the basis of having poorly differentiated carcinoma or poorly differentiated adenocarcinoma. In addition, many were young and had clinical features suggestive of germ cell tumors (eg, location in the mediastinum or retroperitoneum, elevated serum human chorionic gonadotropin or alpha-fetoprotein levels). In selecting this group, we initially suspected that Her-2 overexpression might be more common in poorly differentiated carcinomas than in adenocarcinomas, because overexpression in breast cancer is correlated with poorly differentiated tumors and aggressive clinical course. However, Her-2 overexpression in this group was more common in poorly differentiated adenocarcinomas (22%) than in the poorly differentiated carcinomas with no features of adenocarcinoma (4%). Another interesting finding in this series of patients is that almost all patients with Her-2 overexpression had predominant tumor sites of involvement above the diaphragm, usually in the mediastinum or lungs. Some of these patients may have had non–small-cell lung cancer, known in some patients to overexpress Her-2, but the primary tumor site in these patients was never identified. Because the patients whose tumors were studied in this series were not representative of the general population of patients with carcinoma of unknown primary site, further evaluation is necessary to define the incidence of Her-2 overexpression, particularly in the subset of patients with adenocarcinoma. The finding in this study that most of the Her-2 overexpressors had poorly differentiated adenocarcinoma suggests that the incidence in an unselected group of unknown primary patients (with adenocarcinoma as the predominant histologic finding) may be higher than reported here. The trastuzumab monoclonal antibody should be evaluated in patients with carcinoma of unknown primary site who are overexpressing Her-2, because this treatment may offer an additional effective option in this generally poorly treated group. We are currently evaluating trastuzumab as second-line therapy in these patients. If evidence of clinical activity is documented, we plan to incorporate this antibody into our current combination regimens for first-line therapy.
Supported in part by grant no. X1250n from Genentech, Inc, South San Francisco, CA, and the Minnie Pearl Cancer Foundation, Nashville, TN.
1. Coussens L, Yang-Feng TL, Liao YC, et al: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu-oncogene. Science 230:1132-1139, 1985
2.
Slamon DJ, Godophin W, Jones LA, et al: Studies of the Her-2 proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989 3. Varley JM, Swallow JE, Brammar WJ, et al: Alternatives to either c-erb2 (neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. Oncogene 1:423-430, 1987[Medline] 4. Paik S, Hazan R, Fisher ER, et al: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: Prognostic significance of c-erbB2 protein overexpression in primary breast cancer. Clin Oncol 8:103-112, 1990
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Allred DC, Clark GM, Tandon AK, et al: HER-2/neu in node-negative breast cancer: Prognostic significance of overexpression influenced by the presence of in situ carcinoma. J Clin Oncol 10:599-605, 1992
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Weiner DB, Nordberg J, Robinson R, et al: Expression of the neu gene-encoded protein (P185neu) in human non-small cell carcinoma of the lung. Cancer Res 50:421-432, 1990 7. Sun XF, Carstensen JM, Nordenskjold B: Expression of c-erbB-2 and p53 in colorectal adenocarcinoma. Pathol 8:203-211, 1995 8. Cobleigh MA, Vogel CL, Tripathy D, et al: Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 17:97a, 1998 (abstr 376) 9. Slamon D, Leyland-Jones B, Shak S, et al: Addition of Herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: A randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 17:98a, 1998 (abstr 377) 10. Nystrom JS, Weiner JM, Wolf RM, et al: Metastatic and histologic presentations in unknown primary cancer. Semin Oncol 4:53-68, 1977[Medline] 11. Hainsworth JD, Johnson DH, Greco FA: Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: Results of a 12-year experience at a single institution. J Clin Oncol 10:912-922, 1992[Abstract] 12. Einhorn LH, Donohue JD: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 87:293-301, 1977 13. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435-1440, 1987[Abstract] 14. Greco FA, Hainsworth JD: Cancer of unknown primary site, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA,Lippincott-Raven Publishers, 1997, pp 2423-2443 15. Ellerbroek N, Holmes F, Singletary E, et al: Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 66:1481-1491, 1990 16. Eltabbakh GH, Piver MS: Extraovarian primary peritoneal carcinoma. Oncology 12:813-819, 1998[Medline] 17. Greco FA, Vaughn WK, Hainsworth JD: Advanced poorly differentiated carcinoma of unknown primary site: Recognition of a treatable syndrome. Ann Intern Med 104:547-551, 1986
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Goldberg RM, Smith FP, Ueno W, et al: 5-Fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary. J Clin Oncol 4:395-399, 1986 19. Milliken ST, Tattersall MH, Woods RL, et al: Metastatic adenocarcinoma of unknown primary site: A randomized study of two combination chemotherapy regimens. Oncol 23:1645-1653, 1987 20. Lenzi R, Raber MN, Frost P, et al: Phase II study of cisplatin, 5-FU, and folinic acid in patients with tumors of unknown primary origin. Eur J Cancer 29A:1634-1638, 1993 21. Hainsworth JD, Erland JB, Kalman LA, et al: Carcinoma of unknown primary site: Treatment with one-hour paclitaxel, carboplatin, and extended schedule etoposide. Oncol 15:2385-2394, 1997. Submitted April 29, 1999; accepted August 24, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
