New Treatments for the Management of Treatment-Experienced Breast Cancer: Examining the Evidence
J. Aubrey Waddell, PharmD, FAPhA, BCOP*
Breast cancer is the most commonly diagnosed cancer in women, with an estimated 178 480 new cases of invasive breast cancer and 62 030 new cases of in situ breast cancer diagnosed in women in the United States in 2007.1 Breast cancer is the second most common cause of cancer death in women in the United States after lung cancer. In 2007, an estimated 40 460 women (and 450 men)–approximately 20% of women with the diseaseÑwill likely die from breast cancer.1
However, the incidence of death from breast cancer has declined steadily in the past 20 years as a result of a combination of earlier detection through screening mammogram and improved treatment.1 Perhaps most impressive is that the percentage of women with metastatic disease surviving at least 5 years has increased from 17% in the 1970s and 1980s to 26% today.2 Even between the early and late 1990s the survival rate of women diagnosed with metastatic breast cancer improved by approximately 30%. The improved survival rates have been specifically linked to newer systemic therapies available for this population.3
The greatest risk factor for breast cancer is age. Other risk factors include ovarian function history (age at first menarche, menopause, first birth, and number of live births),4,5 history of benign breast disease,4,6 atypical hyperplasia,7,8 breast density,9 the use of postmenopausal hormones,10 radiation exposure,8 obesity,11,12 and the use of alcohol.13,14 Approximately 5% to 10% of all breast cancers are directly linked to germline mutations in either BRCA1 or BRCA2 genes. Women with these mutations have a 55% to 87% lifetime risk of breast cancer.15-17 Overall, approximately 20% of all breast cancers have some genetic basis.4,18
Breast cancer is typically diagnosed on mammogram or through a clinical or self breast examination. Screening mammography for breast cancer in women aged 40 to 70 reduces mortality from the disease, particularly in older women with the highest risk. It also may identify certain risk factors, such as dense breasts or benign breast disease, that may increase a woman's risk of the disease.19 Such screening programs are a major reason for the overall drop in breast cancer mortality rates because they identify tumors at an earlier stage, when they are most likely to respond to treatment.1
Breast cancer treatment depends on the stage at which it is discovered, tumor size, location, and other characteristics. Treatment typically begins with surgery, either lumpectomy or mastectomy (with or without axillary lymph node removal). Adjuvant treatment typically involves radiotherapy, chemotherapy, hormonal therapy, and targeted therapies.
A greater understanding of the biochemical underpinnings of breast tumors has led to the development of new treatments and treatment protocols, which are enabling women with metastatic breast cancer to live significantly longer than in the past.3 This issue of University of Tennessee Advanced Studies in Pharmacy provides complete coverage of a roundtable held in Scottsdale, Arizona, on September 6, 2007, which included educational presentations followed by lively discussions. The goal of this roundtable was to provide the latest information concerning advances in treatments for advanced or metastatic breast cancer, both current and future.
Robert J. Ignoffo, PharmD, FASHP, FCSHP, from the University of California at San Francisco and Touro University in Vallejo, California, opened with a brief overview of the epidemiology of breast cancer, noting a 50% improvement in the survival rate of women with metastatic breast cancer between 1970 and 2000. He described the clinical course of metastatic breast cancer and the various prognostic factors, including tumor receptor status.
Dr Ignoffo also outlined the treatment goals of metastatic breast cancer, which are primarily palliative, and current treatment options for metastatic breast cancer. These occasionally include surgery and radiotherapy, but are more likely to involve endocrine options and chemotherapy, as well as bisphosphonates for bone metastases. Although patients may use alternative therapies, there is little evidence as to their efficacy.
Dr Ignoffo also discussed the principles of treating metastatic breast cancer with systemic chemotherapy, noting that the growing arsenal of drugs available in the past decade has changed the paradigm of treatment. Then he provided information on the major chemotherapy classes: the anthracyclines, taxanes, fluoropyrimidines, and the targeted therapies trastuzumab and lapatinib. However, he noted that there is no evidence suggesting a benefit of one drug regimen or combination of drugs over others for this stage of breast cancer. He also briefly reviewed the antiangiogenesis agents (eg, bevacizumab and capecitabine) and the use of metronomic chemotherapy, as well as novel or investigational agents.
Nelly G. Adel, PharmD, BCOP, of Memorial Sloan-Kettering Cancer Center in New York, then presented on epothilones, novel cytotoxic agents currently under investigation for metastatic breast and other advanced cancers. She briefly reviewed the development of breast cancer chemotherapy from the 1970s to today, noting that although great progress had been made, there is still far to go. Dr Adel predicted that in addition to considering hormone receptor- and human epidermal growth factor receptor 2-status in determining treatment, clinicians would begin considering other oncogenic signaling, such as PI3K/PTEN/Akt.
Dr Adel then reviewed the importance of microtubules in cellular replication and how taxanes and vinca alkaloids target microtubules, thus interfering with replication. She then introduced the epothilones, a new class of nontaxane microtubule-stabilizing agents, and explained their discovery, chemical structure, and mechanism of action. She spent the rest of her talk describing phase I through III clinical trials of the epothilone, ixabepilone, which is a semisynthetic analog of epothilone B that has demonstrated efficacy in taxane-resistant breast tumors. This compound also may have a role to play in the neoadjuvant breast cancer setting.
Next, Virna Almuete, PharmD, of the Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital in Baltimore, Maryland, discussed the pharmacistÕs role in the care of patients with metastatic breast cancer. She covered common adverse reactions to treatment, including neutropenia and neurotoxicities, focusing on their identification and evaluation, and potential interventions, particularly as they relate to the pharmacist's role. She also addressed the major issue of nonadherence (previously known as "noncompliance") in which patients do not take their medication as directed. This will become a greater issue as more chemotherapy drugs are developed in oral form, she predicted, thus requiring greater pharmacist involvement to maximize adherence. Overall, she noted, patient adherence to oral anticancer drugs ranges from 20% to 100%. Women of advanced age, a different culture, and/or with chronic conditions, as well as those with literacy, language, and/or financial issues, and those providing significant support for others, have the greatest risk of nonadherence.
The roundtable ended with a case study of refractory breast cancer. William C. Zamboni, PharmD, PhD, of the University of Pittsburgh Cancer Institute, described a 69-year-old African American woman with relapsed breast cancer. He described her previous treatment with doxorubicin, docetaxel, cyclophosphamide, and anastrozole, and led the group in a discussion about the patient's remaining option, the nanoparticle formulation of paclitaxel. The rest of the discussion focused on paclitaxel and other nanoparticle and carrier-mediated anticancer agents and their role in metastatic breast cancer. These agents provide prolonged duration of exposure in the patient, Dr Zamboni noted, although their actual mechanism of action is unknown.
In addition, each article and the case study are followed by the corresponding discussion session, which also included John G. Kuhn, PharmD, FCCP, BCOP, of the University of Texas College of Pharmacy in Austin; Patrick J. Medina, PharmD, BCOP, of the University of Oklahoma College of Pharmacy in Oklahoma City; and Dominic A. Solimando, Jr, MA, BCOP, from Oncology Pharmacy Services, Inc. These discussions provide additional insights into the treatment of patients with breast cancer.
1. American Cancer Society. Cancer Facts & Figures, 2007. Atlanta, GA: American Cancer Society; 2007.
2. Giordano SH, Buzdar AU, Smith TL, et al. Is breast cancer survival improving? Cancer. 2004;100:44-52.
3. Chia SK, Speers CH, D'yachkova Y, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2007;110:973-979.
4. Vogel VG. Management of the high-risk patient. Surg Clin North Am. 2003;83:733-751.
5. Sharpe CR. A developmental hypothesis to explain the multicentricity of breast cancer. CMAJ. 1998;159:55-59.
6. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879-1886.
7. Hartmann LC, Sellers TA, Frost MH, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005; 353:229-237.
8. Hollingsworth AB, Singletary SE, Morrow M, et al. Current comprehensive assessment and management of women at increased risk for breast cancer. Am J Surg. 2004; 187:349-362.
9. Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356:227-236.
10. Writing Group for the Women's Health Initiative I. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the WomenÕs Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
11. Carmichael AR. Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG. 2006;113:1160-1166.
12. Lahmann, Lissner L, Gullberg B, et al. A prospective study of adiposity and postmenopausal breast cancer risk: the Malmš diet and cancer study. Int J Cancer. 2003;103:246-252.
13. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998;279:535-540.
14. Hamajima N, Hirose K, Tajima K, et al. Alcohol, tobacco and breast cancer–collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 2002;87:1234-1245.
15. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995;56:265-271.
16. Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68:700-710.
17. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401-1408.
18. Ozanne EM, Klemp JR, Esserman LJ. Breast cancer risk assessment and prevention: a framework for shared decision-making consultations. Breast J. 2006;12:103-113.
19. National Cancer Institute. Breast Cancer (PDQ): Screening. Last updated: April 16, 2007. Available at: http://www.cancer.gov/cancertopics/pdq/screening/breast/healthprofessional. Accessed August 6, 2007.
*Associate Professor, University of Tennessee College of Pharmacy, Oncology Pharmacist, Blount Memorial Hospital, Maryville, Tennessee.
Address correspondence to: J. Aubrey Waddell, PharmD, FAPhA, BCOP, Associate Professor, University of Tennessee College of Pharmacy, Oncology Pharmacist, Blount Memorial Hospital, 2119 Scarlet Rose Court, Maryville, TN 37801. E-mail: JWaddell@bmnet.com.
The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his/her article and all its contents.