New Radiation Therapy for HER-2-overexpressing Breast Cancer

Institution: University of California, Los Angeles
Investigator(s): Richard Pietras, M.D., Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5JB-0105 Award: $200,000
Award Type: IDEAS II
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (1999)
Radiation therapy is an important component in breast cancer management in most patients. Patients treated with breast conservation surgery routinely receive additional therapy with external beam radiation. After total mastectomy with dissection of the lymph nodes, radiation therapy is also recommended for women with large primary tumors, extension of tumor beyond the lymph nodes, or the occurrence of tumor in four or more lymph nodes. The other important role of radiation therapy is in the palliation of symptoms caused by either the primary tumor or metastatic spread of the tumor to distant sites, such as bone. Radiation therapy generally causes injury to the DNA of breast cancer cells. In most cases, this radiation-induced DNA damage is irreversible, and the irradiated cancer cells are killed. However, in other cases, the cancer cells manage to repair the radiation-induced damage to their DNA, and the malignant cells then continue to grow and spread. The latter condition leads to higher chances for relapse of the breast cancer in the affected patient. In fact, some recent clinical studies show that the risk for breast cancer recurrence after treatment with surgery and radiation is higher among breast cancer patients with tumors demonstrating an abundance of a particular marker protein, termed HER-2. This protein is present at the blood surface of the cancer cell and acts as an antenna to attract growth-promoting signals from outside the cell. Abnormally high levels of the HER-2 growth-promoting protein can be found in 25-30% of human breast cancers. A new FDA-approved treatment for the management of patients with metastatic breast cancer is an antibody directed against this HER-2 protein. This new biologic agent, called Herceptin, can be used alone or in combination with certain chemotherapy drugs. Recent studies from our laboratory suggest that therapy of HER-2-overexpressing breast cancers with Herceptin enhances tumor sensitivity to radiation. In addition, combined therapy with Herceptin and radiation causes tumor remissions in breast cancers that failed treatment with radiation alone. This benefit appears to be specific to cells with large amounts of HER-2 and does not occur in cells with normal amounts. A clinical advantage may be achieved in combined Herceptin-radiation therapy if Herceptin selectively radiosensitizes tumor cells or if the two agents act additively and selectively. The possibility that radiation and Herceptin could act selectively against certain breast tumor cells is the subject of the present proposal.

We propose to further evaluate Herceptin-induced radiosensitivity and plan to conduct extensive preclinical studies to evaluate the safety and efficacy of this new therapy. In addition, we hope to learn more about molecular events associated with radiation-antibody treatment in order to further improve utilization of this innovative approach. Human cancer cells damaged by radiation may be especially vulnerable to injury if they are also deprived of essential growth-promoting signals provided by the HER-2 growth promoting protein. We plan to exploit this weakness in HER-2-overexpressing breast cancers in order to develop a new approach to radiation therapy with better clinical outcome and quality of life for affected breast cancer patients in California and elsewhere.

This project proposes an innovative treatment modality that has not been used before. The research team is multidisciplinary, with primary contributions from clinical investigators in Intenal Medicine and Medical Oncology and Radiation Oncology. The impact of this preclinical trial is truly translational. The proposed research exploits a postulated DNA repair-regulatory circuit involving cell surface HER-2 proteins and is intended to lead directly to clinical trials of radiation therapy in combination with Herceptin in patients with HER-2-overexpressing breast cancers.

Final Report (2003)
Radiation therapy is important in the clinical management of breast cancer, but tumor recurrence often occurs despite treatment. Patients with cancers that have high levels of HER-2 growth factor receptor have a high risk for relapse if treated only with radiation and surgery. HER-2 overexpression occurs in 25-30% of human breast cancers and correlates with poor outcome. In tumors with high HER-2 levels, HER-2 receptor antibodies reduce tumor growth. These antibodies, termed Herceptin or Trastuzumab®, are proteins that bind HER-2 receptor at the cell surface and interfere with transmission of growth-promoting signals from outside the cell to genes in the cell nucleus. When given to patients with HER-2-containing cancers, Herceptin promotes extended survival. Laboratory studies show that Herceptin and other agents that block conduction of specific growth-promoting signals may enhance the sensitivity of HER-2-containing tumors to radiation, exceeding remission rates of radiation given alone. From results of this research work, we now provide evidence for the potential clinical utility of Herceptin-induced radiosensitivity and offer new data on specific molecular events both inside and outside the cancer cell that may be associated with this phenomenon.

Conditions for maximal tumor cell killing by Herceptin combined with radiotherapy have been determined in the body. Studies of MCF-7 and ZR75-1 human breast cancer cells with and without high levels of HER-2 show that schedules for administration of Herceptin and radiation are critical for promoting antibody-induced potentiation of radiosensitivity in HER-2-containing cancers. Enhanced killing of tumors with excess HER-2 was found only if Herceptin and radiotherapy were administered in close temporal proximity. A lethal response to radiation is commonly due to radiation-induced injury to cell DNA, but tumors can survive radiation damage by stimulating DNA repair pathways, a process analogous to fixing your wrecked automobile at the repair shop. Herceptin appears to block this process by altering intracellular signals from protein enzymes and by interfering with p21WAF1-induced DNA repair in HER-2-containing tumors, thus allowing cancerous cells to succumb to lethal effects from radiation-induced DNA damage. The protein, p21WAF1, is an important mediator of DNA repair and cell death, and it has critical amino acid residues that are altered by Herceptin therapy.

Another important consequence of high levels of HER-2 in breast cancer cells is the excessive secretion of growth factors for surrounding blood vessels. These vascular cell growth factors promote increased proliferation of blood vessels (angiogenesis) associated with the tumor in order to foster sustained tumor growth. New studies show that combination of Herceptin with biologic agents that block tumor-associated angiogenesis can also significantly amplify the lethal effects of radiotherapy. Collectively, the several novel results of this work may lead to new clinical approaches to reduce the morbidity and mortality of those patients with HER-2-overexpressing breast cancers in California.

Symposium Abstract (2003)
Management of human breast cancer often includes chemotherapy and radiation therapy (RT). However, despite these interventions, patients with cancers overexpressing HER-2 growth factor receptor have a high risk of relapse, and improved treatment approaches are needed. Overexpression of HER-2 occurs in 25-30% of breast cancers. In tumors with high HER-2 levels, antibody proteins to HER-2 receptor, termed Herceptin or Trastuzumab, bind with cell surface HER-2 receptor and interfere with transmission of growth-promoting signals from outside the cell to genes in the nucleus. When given to patients with HER-2-containing cancers, Herceptin promotes extended survival. In laboratory studies of breast cancers with overexpression of HER-2, Herceptin also appears to modulate tumor sensitivity to RT and to certain chemotherapeutic drugs. Herceptin promotes enhanced sensitivity of HER-2-overexpressing tumors to RT, exceeding rates of remission obtained with RT alone. Herceptin treatment also improves the tumor response to cisplatin, carboplatin and taxanes, and this benefit is specific to tumors with overexpression of HER-2. Common biologic mechanisms may underlie such Herceptin-enhanced sensitivity to radiation and chemotherapy. Treatments with RT, platinum agents and taxanes have all been reported to promote damage to cellular DNA. In the normal cell, this event activates DNA damage-control pathways, involving the action of specific proteins, termed cyclin-dependent kinase (cdk) inhibitors. These inhibitors include p21WAF1 and p27kip1, and they function to put the brakes on cell proliferation and evoke a cell resting phase that allows repair of DNA damage. If the cell is unable to successfully repair itís DNA, a program of cell death is activated in order to protect genomic integrity. In HER-2-overexpressing cells, p21 and p27 are altered or excluded from the nucleus where they normally control the cell replication apparatus. These HER-2-dependent alterations appear to promote, in part, non-stop cell proliferation and tumor resistance to RT and chemotherapies. Herceptin treatment of HER-2-overexpressing tumors may reverse this aberrant process by changing the phosphorylation state of the cdk inhibitors and/or their intracellular location, thus allowing normal cell signaling pathways to function. This leads to either the termination of cell proliferation or to cell death. Further understanding of the biologic effects of Herceptin may lead to new approaches to reduce the morbidity and mortality of those patients afflicted with HER-2-overexpressing breast cancers.

[Supported by California BCRP funding].

Steroid hormone receptors in target cell membranes
Index Medicus: Endocrine
Authors: Pietras RJ, Nemere I, Szego CM
Yr: 2001 Vol: 14 Nbr: Abs: Pg:417-427

Epidermal growth factor receptor and tyrosine phosphorylation of estrogen receptor
Index Medicus: Endocrine
Authors: Marquez DC, Lee J, Lin T, and Pietras RJ
Yr: 2001 Vol: 16 Nbr: 2 Abs: Pg:73-81