Disease-free and overall survival have improved significantly for women diagnosed with early-stage breast cancer. At the same time, systemic therapy has only slightly enhanced long-term outcomes in advanced breast cancer, a disease that remains largely incurable. Several single-agent and combination chemotherapy approaches are available to women with hormone-insensitive advanced disease that may improve overall survival and progression-free survival, minimize symptoms and complications related to the disease, and improve overall quality of life. In addition, new cytotoxic and targeted agents have been recently introduced into practice and have improved both survival outcomes and quality of life. In this review, we will provide an update on commonly used chemotherapy-based regimens for the treatment of metastatic breast cancer, with a focus on tailoring therapy to different subtypes of the disease.
Breast cancer continues to be the most commonly diagnosed malignancy in women in the United States, and is the second leading cause of cancer-related death in women, with 40,460 deaths expected in 2007. Notably, breast cancer–related mortality rates have declined from 33 per 100,000 women-years in 1989 to 25 per 100,000 women-years in 2003. The reduction in mortality rates is attributed mostly to the implementation of screening mammography and to optimal local and early systemic therapy. Yet many women suffer a systemic recurrence of their disease, and others present with metastases at the time of initial diagnosis. Despite advances in systemic treatment during the past 30 years, metastatic breast cancer is still considered an incurable disease, with very few exceptions.
Goals of Therapy
The main treatment modality for metastatic breast cancer is systemic therapy, which is administered to achieve one or more aims (Table 1). The ultimate goal of treatment in both the adjuvant and metastatic settings is cure. However, the majority of patients with advanced breast cancer will experience disease progression within 12 to 24 months after treatment initiation, and only a minority (1%–3%) are expected to survive 20 years.
Because cure is a rare outcome in the metastatic setting, it is not usually presented to women as a primary intent. The main goals of therapy therefore shift to improvement of overall survival, time to progression, time to treatment failure, and overall response rate. It is possible, however, that with the introduction of targeted agents, some women may enjoy long-term remissions and may be indeed cured of their disease.
In addition, a large focus of treatment is to control disease-related symptoms and to decrease the risk of serious complications while minimizing toxicity. To achieve these goals, local therapies, such as surgery or radiation, may also be utilized. Because cures are uncommon, quality-of-life considerations are of vast importance and the therapeutic index of a chosen therapy plays a major role in treatment recommendations.
Prognostic and Predictive Factors
Prognostic and predictive factors are used to determine the most appropriate treatment for an individual. Prognostic factors are used to estimate outcome for a patient independent of systemic treatment. Classical prognostic factors in the metastatic setting include time to recurrence, extent of the disease, its location, prior therapy, symptoms related to the disease, and performance status. Hormone receptor status and human epidermal growth factor receptor type 2 (also known as HER2, HER2/neu, or c-erbB2) status are also prognostic factors. In contrast, predictive factors reflect the resistance or sensitivity of a given tumor to a specific therapy. Predictive factors that are currently in use to determine treatment include hormone receptor and HER2 status. Response to prior regimens and performance status are also predictive of treatment efficacy and tolerability.
Only a few investigations provide evidence-based data regarding the long-term outcome of women with metastatic breast cancer, as median survival exceeding 3 to 5 years is the exception. Whether chemotherapy improves overall survival has been the subject of much debate. Obtaining such data is not generally possible because placebo-controlled trials are not ethical in this population. Recent experience suggests that new treatments or schedules are associated with incremental improvement in overall survival. It is important to note, however, that most trials in the metastatic setting exclude women with poor prognostic features or a poor performance status.
Using data from the British Columbia Cancer Agency, Chia and colleagues recently examined survival rates of patients with metastatic breast cancer who received newly introduced hormonal and chemotherapeutic agents over the past 2 decades. The investigators reported that the implementation of new substances and therapies have led to a significant improvement in survival from a population-based perspective.
A cohort of 834 patients who were included in five consecutive anthracycline-based adjuvant protocols at the M.D. Anderson Cancer Center and who subsequently developed recurrent metastatic disease between 1974 and 2000 showed a statistically significant improvement in survival when grouped according to the time of onset. The variables that predicted for longer survival in this cohort included a smaller initial tumor size, lower stage of disease, fewer involved lymph nodes, longer disease-free interval, estrogen receptor–positive tumors, and a nonvisceral dominant site of disease recurrence. Overall, the estimated 5-year survival for patients with bone metastasis was 23%, as compared to 13% for patients with visceral metastasis.
Interestingly, neither the dominant site of disease nor the disease-free interval were significant factors in a study reported by the European Organisation for Research and Treatment of Cancer (EORTC). The EORTC investigators evaluated 75 patients who had achieved a complete response following combination chemotherapy or chemoendocrine treatment for metastatic breast cancer. With a median follow-up of 6 years, the authors reported that 20% of patients who achieved a clinical complete response were alive at 5 years.
M.D. Anderson Cancer Center investigators reported that in a single prospective study, 24% of women who were treated with systemic anthracycline-based therapy following locoregional salvage therapy (surgical resection with or without radiation) of a solitary metastasis (ie, stage IV disease without evidence of disease, or stage IV NED) enjoyed a 15-year disease-free survival. More than half of the metastases included chest wall recurrences. Overall, 36% to 52% of patients with solitary metastases had no evidence of metastatic disease after locoregional treatment of a recurrence after 5 years.
Another study supports a mastectomy in addition to systemic therapy in women with limited advanced disease. Together, these data suggest that an aggressive approach may be a reasonable option for a select group of women and may improve long-term outcomes.
In other studies, the amplification of HER2 was found to be a prognostic factor with greater value than the commonly used factors, such as hormonal receptor status and lymph node–positive disease, both in early and advanced breast cancer.[9,10] In the next decade, high throughput technologies may lead to identification of other prognostic factors. Breast cancer can be divided into several subtypes based on histopathologic features, biologic patterns, and gene-expression profiles. The designation as a specific tumor subtype may become an important factor for determination of prognosis and for treatment decision-making.
Predictive Factors and Breast Cancer Subtypes
The expression of biologic markers on tumor cells is an important feature with respect to the choice of therapy. The most powerful accepted predictive factors are the steroid receptors, including the estrogen receptor (ER) and the progesterone receptor (PR); their presence generally indicates the likelihood of response to hormonal manipulations. The ER, now known as ER-alpha, is expressed in approximately 75% of newly diagnosed breast cancers.
Women with disease progression following prior hormonal interventions are not expected to derive additional benefit from such treatments despite the presence of hormone receptors. Women whose tumors do not express hormone receptors and those who have shown progression following hormonal interventions are considered hormone-insensitive and will be recommended chemotherapy-based therapies. During the past decade, other predictive factors have evolved, including expression or amplification of HER2, a strong predictive factor for trastuzumab (Herceptin) efficacy.
HER2, a 185-kilodalton glycoprotein with tyrosine kinase activity, is overexpressed in about 20% of invasive breast cancers. Overexpression or amplification of HER2 is associated with a poor prognosis, even in early node-negative breast cancer. However, the prognosis of women with HER2-positive disease who receive the recently introduced HER2-targeted therapies has improved dramatically.
The utilization of high-throughput technology such as complementary DNA (cDNA) arrays and the availability of targeted therapy have clearly led to changes in the approach to therapy. Breast cancer can now be classified according to gene-expression profiles. Perou and Sorlie described different molecular portraits of human breast tumors on the basis of gene-expression patterns using cDNA microarrays in 2000. They distinguished luminal A and B, the basal-like, the HER2-positive and the normal-like subtypes. According to subtype, prognoses may differ considerably. More importantly, decisions regarding the most appropriate treatment may vary greatly based on the tumor subtype. Knowledge of tumor subtypes is therefore of great importance when discussing treatment recommendations. With a better appreciation of sensitivity and resistance to specific treatments, it is hoped that women may receive the treatment most likely to benefit them upfront.
Determining Therapeutic Approach
Several factors are considered when determining the most appropriate therapy for women with metastatic breast cancer. The extent of metastatic disease, its location, and the symptoms related to the disease are most important. Prior locoregional treatment and systemic therapy must also be considered, as well as time to recurrence. A risk evaluation should be done before discussing a given therapy, to differentiate patients with a low risk from those with a moderate to high risk for rapid progression. Whereas treatment of the former group allows for more slowly-acting substances such as endocrine therapies, the latter group requires treatment with a substantial and quick response. Factors predictive of low or higher risk are the hormone receptor status, HER2 status, disease-free survival, metastatic burden, metastatic site, and the involvement of vital organs.
Several treatments may be recommended in the metastatic setting, including endocrine treatments, chemotherapy, anti-HER2 therapies, antiangiogenic agents, and other novel therapies.
Dr. Stearns has received research support from Novartis and Pfizer.
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