Use of Gene-Expression Profiling to Recommend Adjuvant Chemotherapy for Breast Cancer
Use of Gene-Expression Profiling to Recommend Adjuvant Chemotherapy for Breast Cancer
One of the primary challenges in the treatment of patients with early-stage breast cancer is determining which patients will benefit from adjuvant chemotherapy. Traditionally, treatment decisions have been made based on a combination of tumor characteristics and patient and physician perspectives regarding risks and benefits. Recent technologic advances, including the development of gene-expression arrays, have led to the identification of molecular signatures that provide prognostic information in addition to the basic clinicopathologic features of individual tumors. While these new methods allow for more refined determination of prognosis for an individual patient, few data are available to support use of these new technologies in the clinic for treatment decision-making. At present, data from a single retrospective study are available to support the use of one assay, the 21-gene recurrence score, for decision-making regarding adjuvant chemotherapy. Large, multinational clinical trials are currently ongoing to evaluate the use of two of the multiparameter assays, although it will be many years before oncologists can apply the results of these trials in the clinic.
A primary challenge for medical oncologists treating women with early-stage breast cancer is deciding which patients should receive adjuvant chemotherapy. It would be helpful to identify which patients either will not relapse at all or will relapse without adjuvant chemotherapy (prognosis) and which therapies are most likely to work against specific cancers (prediction), so that only patients who will obtain benefit are exposed to the inherent toxicities. Historically, this assessment of risk of distant metastatic disease has been based on clinicopathologic features of the tumor, such as lymph node involvement and histologic grade. More recently, the development of multiparameter assays has permitted more detailed evaluation of the biology—as opposed to the anatomy—of tumors. This review will discuss the development of these tools, and whether they are ready for use in the clinics to make individual treatment decisions regarding adjuvant chemotherapy.
Adjuvant Systemic Therapy
Breast cancer remains the most common malignancy in women in the United States. However, breast cancer–specific mortality has been decreasing, due in part to earlier detection of disease with screening mammography and to improved treatment of disease with adjuvant systemic therapies.[1,2] Surgery and radiation therapy are curative for the majority of patients, who obtain no additional benefit from adjuvant systemic therapy. Conversely, for those patients at high risk for recurrence, systemic therapy does not necessarily prevent development of distant metastases.
Unfortunately, no prognostic or predictive factor is 100% perfect for determining benefit from a given therapy for an individual patient. Because of this uncertainty, should all patients receive all available therapies? If a patient is willing to accept any toxicity for any benefit then perhaps she should be treated with everything. In reality, however, the majority of patients are willing to forgo some benefit in order to avoid some toxicity, so therapy must be carefully selected.
By querying breast cancer patients who had previously received chemotherapy, several investigators have attempted to determine the smallest absolute chemotherapy benefit that patients are willing to accept, based on their prior treatment experiences.[3-5] For example, one study evaluated breast cancer survivors previously treated with CMF (cyclophosphamide, methotrexate, fluorouracil [5-FU]) for 6 months. As expected, when asked if they would accept treatment with chemotherapy in a number of hypothetical scenarios, most patients stated that they would opt for therapy again when the gains were large (> 10% absolute benefit), and fewer were willing to do so as the odds of benefit decreased. However, more than 50% of patients said they would undergo chemotherapy for as little as a 3% to 5% absolute improvement in outcome, and nearly 50% stated that they would be willing to accept therapy for as little as a 1% absolute benefit.
These results are remarkably similar to two other studies, suggesting that although these results may be confounded since subjects had survived their breast cancer, a large number of women seem to be willing to take chemotherapy for very small potential chances of benefit. Even so, a substantial proportion of patients would not accept therapy for an absolute benefit of less than 10%, and therefore it remains critically important to determine prognosis and prediction as accurately as possible.
Guidelines and Algorithms
Multiple methods are commonly used by clinicians to determine prognosis. Traditionally the key factors used to estimate the risk of distant metastatic disease include lymph node involvement, histologic grade, tumor size, and expression of hormone receptors (HR) and HER2 (erbB2). The TNM staging system, which combines tumor size (T), lymph node status (N), and presence or absence of distant metastasis (M), has been correlated with prognosis.[6,7]
In order to use these factors for clinical decision-making, numerous guidelines have been developed by agencies in both the United States and Europe. The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant chemotherapy for patients with lymph node involvement, for those with HR-negative breast cancer and tumor size > 1 cm, and for those with HR- and HER2-positive disease and tumor size > 1 cm. The NCCN recommends consideration of chemotherapy for patients with tumor size 0.6 to 1.0 cm regardless of HR status, and those with HR-positive and HER2-negative disease and tumor size > 1 cm.
The St. Gallen guidelines differ slightly from those of the NCCN. They recommend adjuvant chemotherapy for patients with HR-positive, high-risk disease or HR-negative, intermediate- or high-risk disease, and recommend consideration of chemotherapy for patients with HR-positive, intermediate-risk disease. High-risk disease is defined as four or more nodes positive with any HER2 status, or one to three nodes positive and HER2 overexpressed. Low risk is considered age ≥ 35, tumor size ≤ 2 cm, grade 1, no angiolymphatic invasion, and HER2-negative.
For example, consider a 55-year-old woman with a 3-cm, grade 1, ER-positive, HER2-negative tumor with four positive lymph nodes. Using the standard prognostic factors outlined above, in the absence of systemic therapy she has an approximately 50% chance of recurrence over the succeeding 10 to 15 years after diagnosis. Using either the NCCN or St. Gallen guidelines, adjuvant chemotherapy followed by hormonal therapy would be recommended for this patient. Now suppose the patient's tumor was 1.5 cm with no lymph node involvement. In the absence of systemic therapy, her 10-year risk of recurrence is approximately 15%. In this situation, adjuvant chemotherapy should be considered in addition to hormonal therapy according to the NCCN guidelines, but only hormonal therapy should be offered according to the St. Gallen guidelines.
In an attempt to make it easier for physicians to apply the guidelines to individual patients, multiple computer-based algorithms and decision aides have been developed.[10,11] With Adjuvant! Online, the most widely used and highly validated program, the treating oncologist inputs information including patient age, comorbidities, tumor size, histologic grade, HR status, and number of positive nodes, and the computer program predicts the 10-year risk of relapse and mortality for the patient. Based on the physician's choice of chemotherapy and/or endocrine therapy regimen, estimated benefit from each systemic therapy modality is given. The algorithm was validated in a large breast cancer registry, and performed well except in very young women. In the example given above, depending on choice of chemotherapy, the estimated absolute benefit from chemotherapy in the first scenario is 6% to 12%, whereas in the second scenario it is only 2% to 4%.
While these guidelines and computer algorithms allow for individualized decision-making for adjuvant therapy based on the clinicopathologic characteristics of a patient's tumor, they are imperfect. The oncologist still lacks the ability to predict for an individual patient whether her disease will relapse, and whether she will obtain benefit from adjuvant chemotherapy. Therefore, newer methods of assessing breast cancer prognosis and need for systemic therapy are required.
Prognosis and Prediction
Taken together, the considerations above highlight the importance of prognostic and predictive factors. Prognostic factors reflect the metastatic potential and/or growth rate of the tumor, and are used to determine patient outcomes without consideration of treatment administered. For example, ER expression is generally considered a favorable prognostic factor, whereas Ki67 is unfavorable. Conversely, predictive factors reflect the sensitivity or resistance of a tumor to a therapeutic agent, and therefore are used to predict which patients are likely to respond to a specific treatment. ER expression is predictive for response to endocrine therapy, whereas HER2 overexpression is predictive for response to HER2-directed therapies, such as trastuzumab (Herceptin).
Indeed, a factor may be favorable for both prognosis and prediction (as in the ER example given above), or may be mixed. For example, HER2 is an unfavorable prognostic factor, but is a favorable predictive factor for response to HER2-directed therapies (Table 1). Until appropriate studies have been performed, however, it can be difficult to know how to use prognostic and predictive factors appropriately in the clinical setting. Prognostic and predictive properties based on currently available data for three common tumor markers are given in Table 1.