Targeted therapy
Chemotherapy
Hormonal therapy
Targeted Therapy
Targeted therapies are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Some targeted therapies block growth signals from reaching cancer cells; others reduce the blood supply to cancer cells; and still others stimulate the immune system to recognize and attack the cancer cell. Depending on the specific “target,” targeted therapies may slow cancer cell growth or increase cancer cell death.
HER2-targeted therapy: Twenty to thirty percent of breast cancers overexpress (make too much of) a protein known as HER2.[1] Overexpression of this protein leads to increased growth of cancer cells. Fortunately, the development of treatments that specifically target HER2-positive cells has improved outcomes among women with HER2-positive breast cancer.
Herceptin® (trastuzumab): Herceptin is an agent that recognizes and binds to HER2-positive cells. The effects of Herceptin are thought to include decreased cell growth and increased cell death.[2] Among women with HER2-positive breast cancer, Herceptin in combination with chemotherapy has been shown to increase response rates and prolong survival compared to treatment with either Herceptin or chemotherapy alone.[3][4][5] For women who have relapsed after prior chemotherapy for metastatic breast cancer, Herceptin can also be used alone. A study among women who had received extensive prior therapy for metastatic breast cancer reported that treatment with Herceptin alone resulted in a partial or complete disappearance of detectable cancer in 15% of the women.[6]
Tykerb® (lapatinib): Tykerb targets HER2 as well as a related protein known as the epidermal growth factor receptor (EGFR). According to the results of a phase III clinical trial, the combination of Tykerb with the chemotherapy drug Xeloda® (capecitabine) resulted in a longer time to cancer progression than Xeloda alone among women with HER2-positive, refractory advanced or metastatic breast cancer.[7] Tykerb is approved for use in combination with Xeloda for the treatment of HER2-positive advanced or metastatic breast cancer that has progressed following prior therapy with an anthracycline, a taxane, and Herceptin.
Avastin® (bevacizumab): Avastin is a targeted therapy that blocks a protein known as VEGF. VEGF plays a key role in the development of new blood vessels. By blocking VEGF, Avastin deprives the cancer of nutrients and oxygen and inhibits its growth. Avastin’s effects on blood vessels may also improve the delivery of chemotherapy to the tumor.
Research indicates that the addition of Avastin to chemotherapy in the treatment of patients with advanced breast cancer produces more anti-cancer responses and longer cancer-free survival than chemotherapy alone. [8]
Chemotherapy for Recurrent Breast Cancer
Patients with recurrent cancer have typically already received chemotherapy as their initial treatment. The first chemotherapy treatment is called “first-line” and additional chemotherapy for cancer that has recurred is referred to as “second-line.” With the exception of instances where initial treatment may have been inadequate, second-line chemotherapy is typically associated with lower response rates and a shorter duration of remission than first-line therapy. Thus, the goal of second-line chemotherapy is to reduce symptoms, improve a patient’s quality of life, and possibly increase survival.
The type of second-line therapy that is selected and its effectiveness depends on which first-line chemotherapy the patient received. In particular, whether or not a patient’s previous treatment contained doxorubicin or a taxane helps determine options for second-line treatment. Patients typically develop resistance to drugs that were previously used to treat their cancer.
Patients previously treated with a taxane: Abraxane®, a new way to deliver paclitaxel, Gemzar® (gemcitabine), or the oral chemotherapy drug Xeloda® (capecitabine) are treatment options for patients who have already been treated with a taxane.
Abraxane™ (nanoparticle albumin-bound paclitaxel): Abraxane employs a new technique for delivering the anti-cancer drug, paclitaxel. It utilizes albumin, the most abundant protein in the body, to deliver the paclitaxel directly to cancer cells. Albumin is a blood protein that is used by the body to transport nutrients and energy to tissues throughout the body. Once the albumin reaches the tissues of the body, it binds to receptors on the surface of the blood vessel and is taken into the tissues, where it delivers its cargo to the surrounding cells. In the case of Abraxane, that cargo is the anti-cancer drug, paclitaxel.
Results of a clinical trial indicate patients with breast cancer that has progressed with taxanes may respond to treatment with Abraxane. Among 75 patients with taxane-refractory disease, half experienced anti-cancer responses with Abraxane treatment. The cancer was stabilized, meaning it didn’t progress, in 40% of patients. While some patients experienced side effects of treatment, three-quarters were able to receive full doses of Abraxane. Severe loss of sensation in hands and feet occurred in 17% of patients, but this condition did not halt treatment for these patients; 77% were able to continue treatment with lower doses of Abraxane.[9]
Gemzar® (gemcitabine): Clinical studies indicate that Gemzar is an active anti-cancer agent in the treatment of patients with recurrent breast cancer that has previously been treated with a taxane. In clinical trials that have evaluated Gemzar as a second-line treatment for breast cancer, approximately one-third of patients had an anti-cancer response. These patients survived an average of 12-18 months.[10][11]
Xeloda® (capecitabine): Xeloda is a well-tolerated, oral chemotherapy drug that can be taken at home for treatment of breast cancer. Research indicates that 20-30% of patients experience a measurable shrinkage of their cancer following treatment with Xeloda. Xeloda is well-tolerated, and the average duration of survival of patients treated with Xeloda is almost 13 months.[12]
Patients not previously treated with a taxane: For patients not previously treated with docetaxel (Taxotere®) or paclitaxel (Taxol®), clinical studies suggest that treatment with one of these drugs, either as a single agent or in combination with other chemotherapy drugs, can reduce cancer symptoms and prolong a patient’s survival compared to other treatments.
Patients with anthracycline-resistant disease: Patients who have stopped responding to anthracyclines, a class of drugs that includes doxorubicin, are said to be anthracycline-resistant. Treatment options for these patients typically include a taxane alone or in combination with another chemotherapy drug.
Abraxane: A clinical trial that directly compared Abraxane to Taxol in the treatment of 460 patients with metastatic breast cancer, more than three-quarters of whom had received prior therapy that included an anthracycline, demonstrated improved outcomes with Abraxane. Abraxane doubled anti-cancer response rates and significantly delayed disease progression with fewer side effects.[13] The group of patients who had received prior therapy experienced the greatest improvement, living 10 weeks longer than those treated with paclitaxel (56 weeks versus 46 weeks).[14]
Taxotere: Results from a large clinical trial indicate that Taxotere produces longer progression-free and overall survival, and more anti-cancer responses compared to Taxol in the treatment of recurrent breast cancer.[15] Taxotere also appears to be as effective as 5-FU/Navelbine, while producing fewer side effects, in the treatment of patients with metastatic breast cancer whose cancer has progressed following anthracycline-based therapy. [16]
Taxotere/Paraplatin: Results of a clinical trial indicate that 61% of patients with anthracycline-resistant disease treated with Taxotere/Paraplatin responded to treatment, and 66% lived one year or more. On average, the cancer progressed 10 months after treatment.[17]
Taxotere/Xeloda: Results of a clinical trial indicate that patients who received Taxotere plus Xeloda treatment had more anti-cancer responses, lived longer, and experienced a longer time before their cancer progressed compared to patients who were treated with Taxotere alone.[18] The results from this trial prompted the Food and Drug Administration (FDA) to approve the combination of Taxotere plus Xeloda for the treatment of metastatic breast cancer that has stopped responding to anthracyclines.
Patients not previously treated with doxorubicin: The chemotherapy drug doxorubicin is one of the most active chemotherapy agents used for the treatment of breast cancer—most patients receive it as part of their initial treatment for breast cancer. However, an individual can only receive a limited number of doxorubicin due to the risk of damage to the heart with increased exposure.[19]
Doxorubicin administered alone or in combination with a taxane may be an effective second-line treatment for patients not previously treated with this drug. Patients who have been previously treated with doxorubicin can receive additional doxorubicin treatment in selected circumstances, depending upon how much prior doxorubicin therapy was administered. Because doxorubicin is known to cause damage to the heart, patients may wish to have their heart function evaluated before electing to receive continued doxorubicin therapy.[20]
Patients resistant to anthracyclines, taxanes, and Xeloda: The chemotherapy drug Ixempra™ (ixabepilone) has been approved as a single agent for the treatment of metastatic or locally advanced breast cancer that is resistant to anthracyclines, taxanes, and Xeloda. Ixempra is also approved in combination with Xeloda for patients who are resistant to anthracyclines and taxanes, and for patients who are resistant to taxanes and cannot tolerate further anthracycline treatment.
Two clinical trials prompted the FDA approval of Ixempra.The first trial evaluated Ixempra as a single agent. This trial included 126 patients with advanced breast cancer who had stopped responding to treatment with an anthracycline, a taxane, and Xeloda. Patients who had HER2-positive cancer had received prior therapy with Herceptin® (trastuzumab) and had stopped responding. Anticancer responses with Ixempra occurred in 12% of patients.[21]
The second trial compared Ixempra plus Xeloda to Xeloda alone in 752 patients who had stopped responding to anthracyclines and taxanes.[22] Treatment with Ixempra plus Xeloda significantly improved progression-free survival compared with Xeloda alone in this group of patients.
Recurrent Breast Cancer
Hormonal Therapy for Recurrent Breast Cancer
Managing Bone Metastases
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References
[1] National Cancer Institute FactSheet. Herceptin® (Trastuzumab): Questions and Answers. Available at: http://www.cancer.gov/cancertopics/factsheet/therapy/herceptin. Accessed October 11, 2007.
[2] Hobday TJ, Perez EA. Molecularly targeted therapies for breast cancer. Cancer Control. 2005;73-81.
[3] Pegram MD, Slamon DJ. Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: Evidence for receptor-enhanced chemosensitivity. Seminars in Oncology. 1999;26:89-95.
[4] Gori S, Colozza M, Mosconi AM, et al. Phase II Study of weekly Paclitaxel and Trastuzumab in Anthracycline-and Taxane-Pretreated Patients with HER2 Overexpressing Metastatic Breast Cancer. British Journal of Cancer. 2004;90:36-40.
[5] Extra J, Cognetti F, Maraninchi D, et al. Long-term survival demonstrated with trastuzumab plus docetaxel: 24 month data from a randomized trial (M77001) in HER2-positive metastatic breast cancer. Proceedings from the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando FL. 2005; Abstract #555t.
[6] 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. Journal of Clinical Oncology. 1999;17:2639-2648.
[7] Geyer CE, Forster J, Lindquist D et al. Lapatinib plus Capecitabine for HER2-positive Advanced Breast Cancer. New England Journal of Medicine. 2006;355:2733-43.
[8] Miller K, et al. E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Proceedings from the 2005 annual meeting of the American Society of Clinical Oncology (ASCO). Presented May 16, 2005 at “late-breaking” session. May 2005.
[9] O’Shaughnessy JA, Blum JL, Sandbach JF, Savin MA, Fenske E, Hawkins MJ, Baylor-Charles A: Weekly nanoparticle albumin paclitaxel (Abraxane) results in long-term disease control in patients with taxane-refractory metastatic breast cancer San Antonio Breast Cancer Symposium, San Antonio, TX. 2004; Abstract #1070.
[10] Spielmann M, Llombart-Cussac A, Kalla S, et al. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001; 60:303-307.
[11] Carmichael J, Possinger K, Phillip P, et al. Advanced breast cancer: A phase II trial with gemcitabine. Journal of Clinical Oncology. 1995;13:2731-2736.
[12] Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. Classic Papers and Current Comments. 2001;5:790-799.
[13] O’Shaughnessy J, Tjulandin S, Davidson N, et al. ABI-007 (Abraxane®), a nanoparticle albumin-bound paclitaxel demonstrates superior efficacy vs. taxol in MBC: a phase III trial (Abstract #44). Proceedings from the 26th annual San Antonio Breast Cancer Symposium ( 12/3/03 ), Abstract #44.
[14] New Antitubulin Agents. Proceedings from the 22nd annual Miami Breast Cancer Conference. Presented by Dr. Perez. Friday February 25, 2005. 2:45 pm. Miami, Florida.
[15] Jones SE, Overmoyer EB, Budd GT, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. Journal of Clinical Oncology. 2005;23:5542-5551.
[16] Bonneterre J, Roché H, Monnier A et al. Docetaxel vs. 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. British Journal of Cancer. 2002;87:1210-1215.
[17] Mavroudis D, Alexopoulos A, Malamos N, et al. Salvage treatment of metastatic breast cancer with docetaxel and carboplatin. A multicenter phase II trial. Oncology. International Journal of Cancer Research and Treatment. 2003;63:207-212.
[18] O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. Journal of Clinical Oncology. 2002:20:2812-2813.
[19] Buzdar AU, Marcus C, Smith TL, et al. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer. 1985;55:2761.
[20] FDA. FDA Oncology Tools Product Label Details in Conventional Order for Doxorubicin. Accessed March 29,2002.
[21] Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a Phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. Journal of Clinical Oncology. 2007;25:3407-3414.
[22] Vahdat LT, Thomas E, Li R, et al. Phase III trial of ixabepilone plus capecitabine compared to capecitabine alone in patients with metastatic breast cancer previously treated or resistant to an anthracycline and resistant to taxanes. Proceedings from the 2007 annual meeting of the American Society of Clinical Oncology. 2007;25:abstract 1006.