Targeted bio weapons in the war against gynecologic cancers

Revolutionary. Stunning. Remarkable. Excited cancer researchers are using adjectives like these to describe the impressive effectiveness of some targeted biological therapies like trastuzumab (better known as Herceptin, Genentech). Trastuzumab, for example, isn't just for fighting breast cancer recurrence in women who overexpress a certain protein anymore; given to this group of women with early breast cancer, it can cut the risk of cancer returning nearly in half.¹ But the enthusiasm engendered by some clinical trials is tempered by other disappointing news. Trastuzumab can do little for women with ovarian cancer, since few of them overexpress that certain protein, ErbB-2 (better known as HER-2/neu).

It's one thing to selectively destroy a cancer cell when it can be clearly identified as such. But that's been nearly impossible to do. At least until now. [Advances in understanding the molecular changes that distinguish cancers from nearby normal host tissues have opened up unique opportunities for developing targeted biological therapies.] These novel "special" agents are designed to inhibit or interfere with the function of specific molecular pathways without which the tumor can't grow, invade, and metastasize. The further good news is that because targeted therapies focus on molecular changes that are fairly specific to cancers, they may also be likelier to have fewer side effects than standard chemotherapy.

Our goal here is to discuss several molecular targeted cancer treatments-like the monoclonal antibody Herceptin for breast cancer-that have already received FDA approval, and some of the many others-including small-molecule inhibitors-now being tested in clinical trials.

Essentially all human cancers arise from a series of genetic changes that culminate in disrupting the normal molecular mechanisms that govern cell growth, death, and senescence. Playing a role in supporting uncontrolled growth are growth factor receptors that span the outside of the cell; these may be overexpressed or mutated to more active forms. The exposure of these growth factors on the outside of cells provides easy access, making them appealing therapeutic targets.^2,3

Monoclonal antibodies (MoAbs) have been developed that bind to the outer part of the growth factor receptors or to the growth factors, and thus prevent the growth factors from binding to their respective receptors. These include cetuximab (Erbitux, ImClone Systems, and Bristol-Myers Squibb), bevacizumab (Avastin, Genentech), and trastuzumab. Alternatively, researchers have also developed small-molecule inhibitors that can penetrate cells, binding to and inactivating the inner part of the growth factor receptors (known as the tyrosine kinase domain)-the part responsible for transmitting signals to stimulate growth. These receptors are also known as tyrosine kinase receptors (TKRs). Among several tyrosine kinase inhibitors (TKIs) previously or currently being evaluated in gynecologic malignancies are gefitinib (Iressa, AstraZenica), erlotinib (Tarceva, Genentech, OSI Oncology), and imatinib (Gleevec, Novartis).

Two types of TKRs that are often activated in cancers are the epidermal growth factor (Erb family) and vascular endothelial growth factor (VEGF) receptor families.

Epidermal growth factor receptor family

The epidermal growth factor receptor (EGFR) family is composed of four similar TKRs: EGFR, ErbB-2 (HER2/neu), ErbB-3, and ErbB-4.⁴ The binding of growth factors to the receptor spurs tyrosine kinase activity and enables the cell's surface to communicate with its nucleus.

Several MoAbs have been developed against members of the EGFR family. As mentioned earlier, ob/gyns are especially interested in trastuzumab, which targets cancer cells that overexpress the receptor protein. By binding to ErbB-2 receptors, trastuzumab can slow the growth and spread of tumors that overexpress this receptor. [In 1998, trastuzumab received FDA approval for patients with metastatic breast cancer whose tumors overexpress the ErbB-2 protein.] ErbB-2 overexpression (2+/3+), analyzed using immunohistochemistry (IHC), was seen in up to 30% of breast cancers.^5,6 Trastuzumab was initially shown to be well tolerated and active in women with heavily pretreated breast cancer.⁷ It has now been linked to a higher incidence of cardiac dysfunction, however.⁸ A recent study has shown that cardiac toxicity is reversible in most patients (94%) and additional treatment with trastuzumab can be resumed after recovery of cardiac function.⁹

Several randomized clinical trials have looked at women with metastatic breast cancer who hadn't previously undergone chemotherapy. When they were given trastuzumab combined with chemotherapy, these women lived significantly (5 months) longer.^10,11 In addition, as we discussed earlier, this regimen dramatically cuts the risk of recurrence for women with high-risk early-stage breast cancer.¹ Women treated with trastuzumab along with standard combination chemotherapy saw a 52% drop in disease recurrence compared to women given chemotherapy alone.

As we touched on earlier, in contrast to breast cancer, ErbB-2 overexpression is uncommon in gynecologic cancers.^12,13 A phase II trial of trastuzumab in ovarian cancer, in which more than 800 patients were screened for ErbB-2 expression, bore this out. Only 11.4% of the women had cancers that exhibited overexpression.¹² In this study, which had an overall response rate of only 7.3%, the clinical value of single-agent trastuzumab in recurrent ovarian cancer was limited by the low frequency of ErbB-2 overexpression and the low rate of efficacy in patients whose cancers did exhibit overexpression.

A less well-studied issue is whether trastuzumab has activity when combined with chemotherapy, which is how it's usually used in breast cancer. As for a phase II study of patients with endometrial cancer, at last report there had been no objective responses in the 23 patients enrolled.¹³ That said, case reports of activity in combination with taxane-based chemotherapy do exist.¹⁴

EGFR is expressed at varying levels on the cell surface in a significant percentage of human cancers, including colorectal, head and neck, breast, ovarian, endometrial, and cervical cancers.^15-17 The FDA has approved several agents that target this receptor or its growth factor: cetuximab (colon cancer), gefitinib (lung cancer), and erlotinib (lung and pancreatic cancers).^18,19 Subsequently, FDA approval for gefitinib for NSCLC was withdrawn. These biological agents are usually given in combination with cytotoxic agents. Cetuximab in combination with carboplatin is currently being evaluated in a Gynecologic Oncology Group (GOG) study of patients with platinum-sensitive ovarian cancer. Both gefitinib and erlotinib have been studied in gynecologic cancers. However, the response rates have been low; in fact, in the GOG ovarian cancer study the only woman who had a response had a mutation of the EGFR.^20,21 These studies highlight the importance of developing scientifically driven assays to identify patients who will respond to targeted therapy.

Other experimental biologic therapies that target the EGFR family include pertuzumab (Omnitarg, Genentech), a MoAb, as well as lapatinib (TyKerb, GlaxoSmithKline), and BMS-599626, both tyrosine kinase inhibitors (TKIs). Pertuzumab binds at the ErbB-2 dimerization domain and prevents ErbB-2 from binding with activated EGFR and ErbB-3 receptors. This ultimately shuts down intracellular signaling by the activated receptors.²² Pertuzumab differs from trastuzumab in many ways: It has a major effect on the role of ErbB-2 as a co-receptor, inhibits multiple ErbB-2-mediated signaling pathways; and doesn't require ErbB-2 overexpression or amplification for activity. Pertuzumab is currently being evaluated in a phase II trial in ovarian cancer patients who have not responded to platinum-based drugs.²³ Similar to pertuzumab, there are several theoretical advantages for using TKIs that inhibit both EGFR and ErbB-2 receptors.²⁴ For instance, the dual inhibitor is capable of inactivating ErbB-2/ErbB-3 herterodimers, whereas as an EGFR-specific inhibitor, it wouldn't be able to prevent these dimer complexes. ErbB-2/ErbB-3 complexes may be involved in the development of chemotherapy resistance. If that does turn out to be the case, our ability to inactivate this complex would be quite a coup.

Antiangiogenic approaches starve malignant tumors

[For tumors to grow larger than 2 mm in diameter, new blood vessels (angiogenesis) must develop to provide essential nutrients.²⁵] Regulation of angiogenesis is complex, with a variety of pro- and anti-angiogenic factors influencing the development and migration of endothelial cells.²⁶ But on balance, these factors are chiefly pro-angiogenic in malignant tumors, thus opening up the opportunity for researchers to develop antiangiogenic treatments that target the specific molecules involved.^27,28

VEGF is one of the most potent pro-angiogenic growth factors. Along with its receptors, VEGFR-1 (FLT-1) and VEGFR-2 (KDR), it's essential not only to embryonic vascular development, but also to regulating both physiologic and pathologic angiogenesis.^29,30 VEGF, and its receptor, VEGFR-2, seem to be the chief regulators of tumor angiogenesis. A monoclonal antibody that targets VEGF, known as bevacizumab, (Avastin) was approved for treating metastatic colon cancer in 2005. As Figure 1 shows, it starves tumors by stopping the blood vessels with essential nutrients from forming. Adding bevacizumab to standard first-line chemotherapy in patients with metastatic colorectal cancer resulted in extending overall survival by 5 months.³¹ Subsequent RCTs have shown longer survival when bevacizumab is added to standard cytotoxic chemotherapy regimens in lung and breast cancer.^32,33 Of course, for gynecologic cancers, this is currently an off-label use.

Most of the news from the three recent trials that evaluated bevacizumab for treating ovarian cancer was exciting. In a phase II study from the GOG that assessed bevacizumab in women who had failed prior chemotherapy, investigators reported a response rate of 18% including three complete responses.³⁴ Another phase II trial that looked at combining bevacizumab with low-dose cyclophosphamide, reported a response rate of 28% and a 6-month progression-free survival of 57%.³⁵ In these two trials the most common adverse events were proteinuria, hypertension, and arterial thrombotic events. These dramatic study results spurred increased enthusiasm for an antiangiogenic approach in treating ovarian cancer.

However, most recently findings from a single-arm phase II study of women with platinum-refractory disease somewhat dampened this enthusiasm, when it reported an unexpectedly high (11%) incidence of bowel perforation (the cause of which is still unclear). Perhaps the extensive intraperitoneal disease involving the bowel or other factors were to blame. However, in view of bevacizumab's promis-ing results in treating ovarian cancer, the GOG is going ahead with a phase III trial to examine whether adding this antiangiogenic approach to carboplatin/paclitaxel chemotherapy improves survival. Bevacizumab is also being evaluated in women with advanced cervical cancer and another trial is being developed for patients with recurrent or persistent endometrial cancer.

Many other antiangiogenic therapies include TKIs that target VEGF receptors (VEGFR). Two examples are sorafenib (Nexavar, Onyx and Bayer) and sunitinib (Sutent, Pfizer). Both of these agents have already shown significant activity in renal cell carcinoma and have been approved by the FDA for this indication.^36,37 The GOG is evaluating sorafenib in a phase II study of patients with recurrent and persistent ovarian or peritoneal cancer. Although the first stage has completed accrual, it's too early to conclude how effective it is.

Thalidomide, an old drug with a bad reputation, is now being evaluated because of its potent anti-angiogenic effects; several trials are evaluating its role in gynecologic cancers.³⁸

Promising agents for gynecologic cancers?

Targeted biological cancer therapies don't stop there. In 2001, the FDA approved imatinib (Gleevec), a TKI with selective activity against several receptor tyrosine kinases, for the treatment of chronic myeloid leukemia (CML) and GIST (gastrointestinal stomal tumors). In these cancers imatinib specifically blocks activity of the BCR-ABL and KIT tyrosine kinases, respectively. The impressive percentage of patients with these cancers with dramatic and prolonged responses has generated a great deal of enthusiasm for targeted biological cancer therapies. The GOG is testing imatinib against several gynecologic malignancies, but it doesn't appear to be active in ovarian cancer, based on preliminary results.

There's also rituximab (Rituxan, Genentech), a monoclonal antibody that selectively targets the CD20 molecule, which is selectively expressed on the surface of B-cells. It's now widely used in treating non-Hodgkin's lymphoma. Although CD20 is not a relevant target in ovarian cancer, CA 125 is. [Another monoclonal antibody-based treatment (Oregovomab, OvaRex ) is being developed to target CA 125, which is expressed on the surface of more than 80% of epithelial ovarian cancers.] The first randomized prospective phase III study failed to show an overall survival benefit when oregovomab was given as maintenance treatment after first-line chemotherapy. However, the news is better for those patients treated with oregovomab who'd been most effectively debulked at initial surgery and who'd responded well to initial chemotherapy. These women had nearly twice the average time to cancer relapse (24 months) compared to controls (only 11 months).³⁹ This agent is currently being studied in additional RCTs in combination with front-line chemotherapy and by itself after front-line treatment.

Other biologic agents have been engineered to target the RAS pathway, matrix metalloproteinases, heat shock proteins, the mitogen-activated protein kinase pathway (MAPK), and cell-cycle regulators.

In short, targeted cancer therapies hold great promise for treating gynecologic cancers. These agents may be more selective, specifically targeting the cancer cell rather than the normal host cells, and thus improve clinical outcome, reduce side effects, and potentially improve the quality of life of our patients. Some clinical trial results have engendered enthusiasm, whereas other results (such as gefitinib) have been beyond disappointing. The gefitinib experience highlights the importance of companion studies that examine molecular effects of targeted therapy in patients treated on clinical trials. [A better understanding of cancer molecular biology will continue to speed the development and implementation of targeted therapies and will allow us to direct treatment toward the patients most likely to benefit from them.]

FREE ONLINE CME

To earn CME credit for this article, participants should read the article and log onto http://www.contemporaryobgyn.net, where they must pass a post-test. After completing the test and online evaluation, a CME credit letter will be e-mailed to them. The release date for this activity is October 1, 2006. The expiration date is October 1, 2007.

CME Learning objectives

Upon completion of this article, participants will be able to:

• Describe three types of targeted biological treatment for gynecologic cancer that have significant promise, based on recent clinical trial results.
• Analyze the role of tyrosine kinase receptors in activating breast and ovarian cancers, as explained in currently available literature, and describe how targeted therapies arrest tumor development by disrupting those mechanisms.
• In conjunction with a specialist, incorporate FDA-approved targeted biological therapies for appropriately selected patients with specific types of gynecologic tumors.

Accreditation

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of AHC Media LLC and Contemporary OB/GYN. AHC Media LLC is accredited by the ACCME to provide continuing medical education for physicians.

AHC Media LLC designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Target audience

Obstetrician/gynecologists and women's health practitioners.

Disclosures

One co-author of this article, Andrew Berchuck, MD, and the manuscript reviewer report no relationships with companies having ties to this field of study. The other co-author, Angeles Alvarez Secord, MD, discloses that she receives grant/research support from Sanofi-Aventis, Amgen, Novartis, Eli Lilly, and Unither, and is also on the Speakers Bureaus of Sanofi-Aventis and Abraxis. The editors (Judith M. Orvos, Elizabeth A. Nissen, and Paul L. Cerrato) disclose that they do not have any financial relationships with any manufacturer in this therapeutic category.

REFERENCES

1. Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC->T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat. 2005;94(suppl 1):S5. Abstract 1.

2. Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355-365.

3. Cohen P. Protein kinases-the major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002;1:309-315.

4. Franklin WA, Veve R, Hirsch FR, et al. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol. 2002;29:3-14.

5. Harries M, Smith I. The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer. 2002;9:75-85.

6. Press MF, Godolphin W, Slamon D. Expression of the HER-2/neu/c-erbB-2 oncogene in breast cancer. Lab Invest. 1989;60:A73.

7. 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. 1999;17:2639-2648.

8. Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005;23:7811-7819.

9. Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center Experience. J Clin Oncol. 2006;24:4107-4115.

10. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792.

11. Eiermann W. Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: pivotal trial data. Ann Oncol. 2001;12(suppl 2):57-62.

12. 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. 2003;21:283-290.

13. Fleming GF, Sill MA, Thigpen JT, et al. Phase II evaluation of trastuzumab in patients with advanced or recurrent endometrial carcinoma: a report on GOG 181B. Proc Am Soc Clin Oncol. 2003;22:453. Abstract 1821.

14. Jewell E, Alvarez Secord A, Brotherton T, Berchuck A. Use of trastuzumab in the treatment of metastatic endometrial cancer. Int J GynecolCancer. 2006;16:1370-1373.

15. Scambia G, Panici PB, Battaglia F, et al. Significance of epidermal growth factor receptor in advanced ovarian cancer. J Clin Oncol. 1992;10:529-535.

16. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183-232.

17. Scambia G, Panici PB, Ferrandina G, et al. Significance of epidermal growth factor receptor expression in primary human endometrial cancer. Int J Cancer. 1994;56:26-30.

18. Cohen MH, Williams GA, Sridhara R, et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa (R) tablets. Oncologist. 2003;8:303-306.

19. Cohen MH, Johnson JR, Chen YF, et al. FDA drug approval summary: erlotinib (Tarceva (R) tablets. Oncologist. 2005;10:461-466.

20. Gordon AN, Finkler N, Edwards RP, et al. Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer. 2005;15:785-792.

21. Schilder RJ, Sill MW, Chen XW, et al. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin Cancer Res. 2005;11:5539-5548.

22. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005;23:2445-2459.

23. Gordon MS, Matei D, Aghajanian C, et al. Clinical activity of pertuzumab (rhuMab 2C4) in advanced, refractory or recurrent ovarian cancer (OC), and the role of HER2 activation status. 2005 ASCO Annual Meeting 2006; Abstract 5051.

24. Druker BJ. Tyrosine Kinase Inhibitors. PPQ Updates. 2005;19(5):1-11.

25. Folkman J. What is the evidence that tumors are angiogenesis dependent? J NatlCancer Inst. 1990;82:4-6.

26. Diaz-Flores L, Gutierrez R, Varela H. Angiogenesis: an update. Histol Histopathol. 1994;9:807-843.

27. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med. 1999;5:1359-1364.

28. Burke PA, DeNardo SJ. Antiangiogenic agents and their promising potential in combined therapy. Crit Rev Oncol Hematol. 2001;39:155-171.

29. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439-442.

30. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435-439.

31. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335-2342.

32. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599. ASCO 41st Annual Meeting. 2005.

33. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. ASCO 41st Annual Meeting. 2005.

34. Burger RA, Sill M, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): a Gynecologic Oncology Group (GOG) study. J Clin Oncol. 2005;23:457S.

35. Garcia A, Oza AM, Hirte H, et al. Interim report of a phase II clinical trial of bevacizumab (Bev) and low dose metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary peritoneal carcinoma: a California Cancer Consortium Trial. J Clin Oncol. 2005;23:455S.

36. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16-24.

37. Favaro JP, George DJ. Targeted therapy in renal cell carcinoma. Expert OpinInvestig Drugs. 2005;14:1251-1258.

38. D'Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082-4085.

39. Berek J, Taylor P, Gordon A, et al. Randomized, placebo-controlled study of Oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. J Clin Oncol. 2004;22:3507-3516.