Biologic Therapy

HER-2/neu is the first widely studied oncogene relevant to breast cancer.¹ Available data strongly suggests that there is a strong association between HER-2/neu overexpression and poor prognosis in patients with node-positive breast cancer.² There is also some evidence that suggests this same association exists in patients with node-negative breast cancer.³ Whether the level of HER-2/neu expression induces either drug sensitivity or resistance has yet to be determined.⁴

Preclinical studies have shown that antibodies directed against the transmembrane glycoprotein coded for by HER-2/neu oncogene (p185^HER-2) can inhibit or arrest the growth of HER-2/neu overexpressing cells.^5-11 Trastuzumab, a humanized murine monoclonal antibody directed against p185^HER-2, is the first such agent to be made available for the treatment of breast cancer. Clinical phase I/II trials have shown that trastuzumab is active in patients with metastatic breast cancer and overexpression of HER-2/neu. In a phase II study of 43 patients with extensive disease, a total of 5 patients responded (1 complete and 4 partial responses) for an overall response rate of 12%. An additional 2 patients had minor responses, and 14 patients had stable disease. Adverse events were rarely more severe than grade 2; only one event was grade 3.¹² In another study, a total of 222 breast cancer patients were enrolled who had relapsed following one or two prior chemotherapy regimens for metastatic disease. The overall response rate observed in this trial was 14% (2% complete, 12% partial response). Complete responses were observed only in patients with disease limited to skin and lymph nodes. In this study, degree of HER-2/neu overexpression was a predictor of treatment effect.¹³

Results from preclinical studies first indicated that trastuzumab may be additive to conventional chemotherapeutic agents.¹² This has now been confirmed in a phase III clinical study of patients receiving trastuzumab and chemotherapy as first-line therapy for metastatic breast cancer.^13,14 A total of 469 patients with metastatic disease and overexpression of HER-2/neu were treated with either an anthracycline plus cyclophosphamide, or paclitaxel as a single agent. Those who received prior anthracycline as adjuvant therapy received paclitaxel; all others received the anthracycline-based combination. Following chemotherapy, half the patients were randomized to receive additional trastuzumab.

Results of this phase III study showed that the addition of trastuzumab to chemotherapy resulted in a significantly longer time to disease progression, a higher overall response rate, a longer median duration of response, and a higher one-year survival rate (Table). While these effects were observed both in patients who received paclitaxel and in those who received an anthracycline-based combination, the magnitude of these effects was greater in the paclitaxel subgroup. In addition, the probability of cardiac dysfunction was highest in patients who received trastuzumab plus an anthracycline-based combination. In both single-agent and combination trials, the degree of HER-2/neu overexpression was a predictor of treatment effect.¹³

Table. Response and Survival Results¹³
 

	Chemotherapy	Paclitaxel Subgroup	Anthracycline/Cyclophosphamide Subgroup
	Trastuzumab + Chemotherapy	Chemotherapy Alone	Trastuzumab + Paclitaxel	Paclitaxel Alone	Trastuzumab + Anthracycline/ Cyclophosphamide	Anthracycline/ Cyclophosphamide Alone
Median time to progression, mo	7.2	4.5*	6.7	2.5*	7.6	5.7*
Overall response rate	45	29*	38	15*	50	38†
Duration of response (Kaplan-Meier estimate)	8.3	5.8	8.3	4.3	8.4	6.4
1-year survival (Kaplan-Meier estimate)	79	68*	73	61‡	83	73*

*P < .05
^†P = .1
^‡P = .08

Based on these findings, trastuzumab is currently indicated in combination with paclitaxel as first-line treatment of metastatic disease in patients whose tumors overexpress HER-2/neu. Trastuzumab is also indicated as a single agent for the treatment of patients with metastatic breast cancer whose tumors overexpress HER-2/neu and who have received one or more prior chemotherapy regimens for metastatic disease.¹³

Future trials are likely to explore novel strategies, such as escalation of dose density, with which to optimize antitumor effect of trastuzumab and reduce potential toxicity. In addition, the encouraging results achieved with this monoclonal antibody will no doubt stimulate further research into other biologic tumor markers, in the hopes of identifying other targets for biologic therapy of breast cancer.
 

References

1. Ravdin PM, Chamness GC. The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers—a review. Gene. 1995;159:19-27.
2. 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. 1998;16:1340-1349.
3. Alred 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. 1992;10:599-605.
4. Pegram MD, Finn RS, Arzoo K, et al. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene. 1997;15:537-547.
5. Hancock MC, Langton BC, Chan T, et al. A monoclonal antibody against the c-erbB-2 protein enhances the cytotoxicity of cis-diamminedichloroplatinum against human breast and ovarian tumor cell lines. Cancer Res. 1991;51:4575-4580.
6. Hudziak RM, Lewis GD, Winget M, et al. p185^HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989;9:1165-1172.
7. McKenzie SJ, Marks PJ, Lam T, et al. Generation and characterization of monoclonal antibodies specific for the human neu oncogene product, p185. Oncogene. 1989;4:543-548.
8. Stancovski I, Hurwitz E, Leitner O, et al. Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci USA. 1991;88:8691-8695.
9. Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185^HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA. 1992;89:4285-4289.
10. Lewis GD, Figari I, Fendly B, et al. Differential responses of human tumor cell lines to anti-p185^HER2 monoclonal antibodies. Cancer Immunol Immunother. 1993;36:255-263.
11. Harwerth I-M, Wels W, Schlegel J, et al. Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth. Br J Cancer. 1993;68:1140-1145.
12. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185^HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14:737-744.
13. Herceptin^® (trastuzumab) anti-HER2 monoclonal antibody. Product information.

Slamon D, Leyland-Jones B, Shak S, et al. Addition of Herceptin&trade; (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. 1998;17:98a. Abstract 377.