Breast Cancer: Radiotherapy and Adjuvant Systemic Modalities
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Despite increased rates of detection and treatment, breast cancer remains the second leading cause of cancer mortality among women. Accurate assessment of an individual's risk for breast cancer is critical in breast cancer prevention efforts. Preventive pharmacologic interventions have proven to substantially reduce breast cancer risk, but it should be noted that the accuracy of individual risk cannot be guaranteed. Tailored treatment and personalized medicine have become the new buzzwords in oncology. Knowledge of breast cancer subtypes and molecular targets have led to extraordinary advances in tailoring systemic therapies. Radiation therapy (RT) plays an important role in management of breast cancer. In all situations, RT must be delivered in a manner that will appropriately treat the target tissues and minimize risks to adjacent normal tissues. For patients desirous of breast-conserving therapy (BCT), lumpectomy plus breast RT is typically the preferred approach, because it provides long-term survival rates equivalent to that achieved with mastectomy. BCT with lumpectomy plus breast RT is appropriate for most women with ductal carcinoma in-situ. Radiotherapy has long played an important role in the management of patients with locally advanced disease. There is also growing recognition of the utility of post-mastectomy radiotherapy (PMRT). Adjuvant systemic therapy for breast cancer has been a primary focus of oncology research for more than 40 years. Breast cancer is an example of a disease that has substantially benefited from the cumulative effect of small incremental improvements involving all available therapeutic modalities, which can explain the recently observed decrease in breast cancer mortality in some countries.
The purpose of this document is to briefly describe the different techniques currently used to treat patients with breast cancer, as well as newer approached that may become more widely used in future. This chapter also briefly reviews our current understanding of the role of adjuvant systemic therapy in the management of breast cancer in the modern era.
In all situations, RT must be delivered in a manner that will appropriately treat the target tissues and minimize risks to adjacent normal tissues (1). Adding definitive breast irradiation after breast conservation surgery is standard practice. A number of different radiation options are now available, including conventional whole-breast radiation treatment, accelerated partial-breast irradiation (APBI). Randomized clinical trial have demonstrated the value of conventional whole-breast radiation treatment with 20-25 years of follow-up and accelerated whole-breast radiation treatment with 10-12 years of follow-up (18). Randomized trials are now ongoing to evaluate APBI. These radiation treatment options now give physician and patients the ability to customize the radiation treatment program to the individual clinical setting, and ongoing randomized trials will provide more guidance in the future for APBI. Adding a radiation treatment boost is another factor that the treating physician can control. The technical approach for the boost field is not well defined, requires a great deal of judgment and is difficult to study. Nonetheless, such boosts can be tailored to individual patients, particularly if a specific margin is not established as pathologically negative. The various techniques currently used are:
Interstitial Implantation: It is also termed as brachytherapy refers to the placement of radioactive materials inside the patient's tissues. These materials typically emit low-energy radiation such that only the limited volume of tissue in the immediate vicinity of the implant is treated. This technique can deliver localized treatment to the tumor bed following lumpectomy for either invasive cancer or carcinoma in-situ, or in some special situations it can be used to irradiate a modest portion of the chest wall. Implants have also been used to treat large portions of the breast to very high doses in patients who have not undergone tumor excision. Implants have usually been used in conjunction with external-beam treatment, although there is growing interest in treating selected patients with implants alone. Breast implants are typically temporary, that is, the radioactive sources are placed in the patient for a finite time and then removed. High-dose-rate (HDR) brachytherapy is becoming very popular. Dose per dose, normal tissue reactions are generally more severe with HDR than with low-dose-rate (LDR) implants. For this reason, HDR therapy is typically delivered in a fractionated manner (e.g., giving multiple treatments spread over a several-day period) to mitigate its effect.
External-Beam Treatment: It is also termed as teletherapy refers to delivery of radiation to a patient from a device located a distance outside the patient. It is the most common method to deliver therapeutic radiation. Two types of external-beam radiation are commonly used: photons and electrons. A variety of radioactive materials theoretically can be used for external-beam photon irradiation. In practice only cobalt-60 provides a photon beam of high enough energy to be clinically useful. A linear accelerators (LINACs) also can generate a therapeutic electron beam. Removing the tungsten target from the path of the electron beam does this. Radioactive isotopes may also emit electrons. However, their energy is typically too small, and thus their depth of penetration is limited to be useful in the management of breast cancer. By varying the energy of the photon or electron beam, one can vary the depth of penetration of these beams. Low-energy photons, such as those emitted from brachytherapy sources (e.g., Ir192) do not penetrate deeply. Most patients receiving RT to the intact breast or chest wall are treated with tangential photon fields to limit exposure of the underlying lungs and heart. "Wedges" which are wedge-shaped pieces of metal, are typically used to attenuate the beam more in some areas than others so as to compensate from the changing slope and thickness of the breast or chest wall and thereby make the distribution of radiation dose more uniform. Before delivering RT, patients undergo treatment planning on a simulator. The simulator has the same geometry as the treatment machine but provides diagnostic quality fluoroscopy. This facilitates the iterative process of field design. More recently, techniques of CT simulation have been developed that allow internal anatomic information to be incorporated into a "three-dimensional" treatment planning process. There is substantial patient-to-patient variation in normal anatomy, which may result in over-treatment of critical normal tissues and/or under-treatment of target tissues when planning is based on surface anatomy, as is done using traditional fluoroscopic simulators. With conventional RT techniques, the dose to the contralateral breast is minimal (2). In the United States and most of Europe, the entire breast of chest wall receives a dose of 46 to 50 Gy delivered in 25 to 28 individual sessions, giving one fraction daily, 5 days per week with a dose of 1.8 to 2.0 Gy per fraction. This "protracted" fractionation schedule appears to reduce the risk of late normal tissue reactions. Some centers advocate a shorter treatment regimen with higher daily dose per fraction and a lower total radiation dose. Following lumpectomy an additional 10 to 15 Gy "boost dose" is often delivered to the tumor bed region because most failures are in this area. This is usually done with an external electron field.
Therapy to the tumor-bed alone: There is a growing interest in using brachytherapy alone to the lumpectomy site, without whole-breast external-beam irradiation, as definitive treatment for both invasive and non-invasive carcinoma. Such localized therapy can also be delivered with focused external-beam electron or photon techniques. The rationale for this approach is that most local recurrences are in the vicinity of the index lesion. RT to the excision cavity, with several surrounding centimeters of normal breast tissue, should therefore in principle provide a high rate of tumor control. This approach however does not address microscopic multifocal disease and is technically challenging. The utility of this approach therefore is unclear because whole-breast RT remains useful even after quandrantectomy (2).
Intraoperative Radiation Therapy: Devices have been developed to allow localized irradiation of the tumor bed, immediately following excision. Such "intraoperative RT" can be done using either low-energy photons or electrons. A trial using a miniaturized radiation source that can be introduced into the lumpectomy cavity is being conducted in England (2).
Intensity-Modulated Radiation Therapy: Traditional RT uses treatment fields that maintain a fairly uniform intensity of radiation dose in the two dimensions perpendicular to the direction of the beam. Newer hardware and software enable the radiation oncologist to adjust the two-dimensional intensity of the radiation beam, thus allowing the dose to be made purposely non-uniform. Such "intensity-modulated radiation therapy" (IMRT) may result in better conformation of the therapeutic dose to the target tissues. This may allow increased sparing of normal tissues and increased control of dose delivery to the target tissues, thus improving the therapeutic ratio of RT.
Prone Positioning and Respiratory Gating: Patients undergoing RT for breast cancer are typically treated in the supine position. Delivering external RT to the patient in the prone position may improve the therapeutic ratio by moving the majority of the breast away from the underlying normal tissues. However, matching of such breast fields to the fields needed to treat the abutting supraclavicular and axillary regions may be challenging. Conventional RT is delivered virtually continuously throughout the respiratory cycle. It is possible to gate therapy such that, the machine is "on" only during a portion of the cycle, such as during deep inspiration. This approach might reduce the amount of lung and heart in the treatment fields without compromising treatment of the target tissues (3).
Radiotherapy without Surgery: Patients with locally advanced breast cancers (LABCs) treated only with external-beam radiotherapy techniques (with or without systemic therapy) have loco-regional failure (LRF) rate of 30% or greater. LRF rates of 10% to 20% have been achieved using high-dose interstitial implantation (20 to 30 Gy) as a boost treatment following external-beam radiotherapy (45 to 50 Gy to the breast and regional lymph nodes). Because very large radiation doses must be given, such treatment may result in a 10% to 20% rate of moderate and severe complications (4). One approach, which has been especially popular in France, is to treat patients who have a complete (or near complete) clinical response to neoadjuvant therapy with radiotherapy alone; no breast surgery of any kind is performed. Local control rates among highly selected patients have been excellent in some series. One difficulty in selecting patients for this approach is the limited reliability of clinical and mammographic examination in detecting residual disease or estimating its volume and extent after neoadjuvant therapy. Small studies have found that magnetic resonance imaging (MRI) has high accuracy in this regard. Both mastectomy (with immediate reconstruction if the patient so desires) and radiotherapy are usually needed to achieve optimal loco-regional control in patients with LABC. It is as yet unknown whether selected patients undergoing mastectomy after neoadjuvant chemotherapy have such a low risk of LRF that post-mastectomy radiotherapy (PMRT) could be omitted. It thus seems prudent at present to use PMRT routinely, even for patients with a pathologic complete response. Only a minority of patients with LABC are candidates for breast-conserving treatment after neoadjuvant therapy. It is unknown whether such patients would have a superior outcome if treated instead with mastectomy. Nonetheless, it seems reasonable to offer breast-conserving treatment to carefully selected patients. Results with approach are likely to be better with excision of tumor than when radiotherapy alone is used.
Radiotherapy and Ductal Carcinoma in-situ: The rationale for treating patients with ductal carcinoma in situ (DCIS) with radiation therapy (RT) following conservative surgery (CS) is that RT can substantially reduce the incidence of tumor recurrence. The effectiveness of such treatment was hindered until recently by the limited available knowledge of the natural history of the disease of factors correlated with improved rates of tumor control. The cause-specific survival rates achieved with CS and RT have been reported to be 95% to 100% (4). This suggests that the long-term efficacy of this treatment approach is similar to that of mastectomy. Multiple retrospective studies and three prospective randomized trials have clearly established the long-term efficacy and role of CS and RT in the management of patients with DCIS. Data from multiple institutions support the value of thorough mammographic/pathologic correlation and the need for careful attention to adequacy of excision in producing optimal long-term results; particularly for younger patients (4). Identification of clinical, pathologic and treatment related factors associated with a greater risk of local recurrence have helped define subsets of patients for whom CS and RT may be less appropriate than mastectomy. Current research goals include establishing which patients do not require RT after CS and the role of tamoxifen.
Radiotherapy and Regional Nodes: Patients with pathologically uninvolved axillary nodes following technically adequate axillary surgery are at low risk of regional nodal failure and should not receive specific nodal irradiation. Supraclavicular irradiation should be given to all patients with four or more positive axillary lymph nodes, given the substantial risk of failure in this area and the difficulty of controlling such recurrences (5). However, there is substantial controversy about whether supraclavicular irradiation should be used routinely for patients with one to three positive axillary nodes. There is no consensus on the value of prophylactic internal mammary nodal irradiation for patients with positive axillary nodes. Radiotherapy is effective in preventing axillary recurrence in patients with clinically uninvolved nodes. Hence, axillary irradiation is a reasonable alternative to dissection for such patients. The rate of serious complications resulting from current doses and techniques of axillary, supraclavicular, and internal mammary nodal irradiation is low.
Adjuvant Systemic Modalities
Breast cancer is an example of a disease that has substantially benefited from the cumulative effect of small incremental improvements involving all available therapeutic modalities, which can help explain the recently observed decrease in breast cancer mortality in some countries. More recently, a greater emphasis has been placed on the role of meta-analyses. Although both randomized clinical trials and meta-analyses are important tools to minimize the effects of bias on the observed results, even the latter can also be affected by the "play of chance". These important developments have forced physicians caring for breast cancer patients to acquire a working knowledge of important biostatistics and methodology principles. Adjuvant systemic therapy includes endocrine manipulation, chemotherapy or both.
Who should not receive Adjuvant Systemic Therapy?
Decisions about whether to offer an individual woman adjuvant systemic therapy should balance her risk of relapse, the possible absolute benefit of therapy, and the importance of other comorbid conditions that may limit her survival or put her at an increased risk for adverse events associated with the treatment. Traditionally, women with early-stage breast cancer with a moderate to high risk of relapse have been offered adjuvant systemic therapy. Tumors from more than 50% of all women diagnosed as having breast cancer will express the estrogen receptor (ER) or progesterone receptor (PR). Although long in duration treatment with tamoxifen or other therapies that reduce estrogen content to the tumor cells is generally well tolerated and almost every woman with hormone receptor-positive invasive breast cancer will benefit from such treatment if contraindications do not exist. Although the risk of chemotherapy-related life-threatening events is small, there are many known and possibly unknown short- and long-term risks of chemotherapy. Based on usual prognostic factors, chemotherapy is recommended to most women with a node-negative breast cancer whose tumor size is at least 2 cm. Women with stage I breast cancer have an improved prognosis overall; however, up to 20% may suffer a recurrence. Thus other prognostic factors need to be considered in treatment factors of this early stage.
Preoperative Systemic Therapy
Chemotherapy in women with early-stage breast cancer has traditionally been administered after definitive breast surgery. Based on the pathologic findings at the time of surgery (e.g., the tumor size, nodal involvement, other characteristics such as grade and receptor status), clinicians can estimate the risk for recurrence and provide treatment recommendations to the patient. Primary chemotherapy (also designated preoperative chemotherapy or neoadjuvant chemotherapy) has traditionally been reserved for women with locally advanced breast cancer to enhance the likelihood of negative surgical margins or even breast preservation (5). Studies of the primary administration of chemotherapy in the locally advanced breast cancer setting have demonstrated that this treatment modality may provide other benefits. The administration of primary chemotherapy enhances the likelihood of breast conservation. Response to primary chemotherapy can be correlated with long-term outcomes such as disease-free-survival (DFS) and overall-survival (OS). Early eradication of micro-metastases may lead to improved DFS and OS either by decreasing the possibility of encountering drug resistance or by producing less favorable growth kinetics. Some have concerns that administration of primary therapy may be associated with the loss of standard prognostic factors such as tumor size or nodal involvement that are generally used to guide treatment recommendations.
Primary therapy may also include endocrine agents. For decades primary therapy with tamoxifen has been used for older women with inoperable receptor-positive tumors. Endocrine therapy offers similar reduction in the annual odds of recurrence and death irrespective of age, menopausal status, tumor size or lymph node status and should be offered to virtually all patients with endocrine-responsive invasive disease. The National Institutes of Health (NIH) Consensus panel made the following recommendations regarding endocrine therapy (6):
- The decision to recommend adjuvant hormonal therapy should be based on the presence of estrogen receptor (ER) or progesterone receptor (PR) as assessed with immuno-histochemical staining, and if insufficient tumor is available for testing, the hormone receptor status should be considered positive, especially in post-menopausal women.
- The expression pattern of the HER2/neu gene should not influence the decision to recommend hormonal therapy.
- Tamoxifen administration is not recommended for women with ER- and PR-negative invasive breast cancers.
- Five-years of adjuvant tamoxifen therapy should be recommended for all women with hormone receptor-positive tumors, regardless of age, menopausal status, axillary lymph node status, tumor size, or use of adjuvant chemotherapy; possible exceptions include women with node-negative tumors smaller than 10 mm who wish to avoid the side effects of tamoxifen.
- Ovarian ablation or suppression may be considered an alternative to chemotherapy in pre-menopausal women.
The Consensus Panel also emphasized that for most women the benefit from adjuvant tamoxifen far outweighs any risk, such as endometrial cancer and venous thromboembolism, and that neither transvaginal ultrasonography nor endometrial biopsy is indicated as a screening test for endometrial cancer in asymptomatic women taking tamoxifen. Much remains to be learned about the optimal use of endocrine agents such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) in the treatment and prevention of breast cancer, alone or in combination with other agents. Biophosphonates reduce the risk for bone-related complications in patients with metastatic disease. Finally, one must not forget that an increasing number of breast cancer patients treated in the adjuvant setting will survive their disease or enjoy a long disease-free-survival (DFS). Therefore continuing efforts should be devoted to further understand the potential long-term effects of adjuvant systemic therapies and to develop strategies to minimize the risk for complications that might negatively affect the quality of life of these patients and negate the benefit gained from the use of adjuvant therapy.
Current Endocrine Therapies for Breast Cancer
It is the most widely used endocrine therapy for the treatment of breast cancer. The US Food and Drug Administration (FDA) has approved it for the treatment of metastatic breast cancer in postmenopausal women; estrogen-receptor-positive; metastatic breast cancer in premenopausal women; and estrogen-positive-receptor metastatic cancer in men. Tamoxifen has also been approved as an adjuvant therapy, either alone or after chemotherapy, for early-stage, hormone receptor-positive breast cancer in premenopausal and postmenopausal women. Tamoxifen is the first drug approved as chemoprevention agent for women at high-risk for breast cancer. The antitumor effect of tamoxifen is mediated primarily through the estrogen-receptor, although other potential mechanisms of action may contribute. The estrogen-responsive gene transcribes and subsequently translated to proteins that are involved in either growth responses or differentiation responses (7). A 20 mg/day dose of tamoxifen is generally viewed as the optimal dose in the advanced, adjuvant, and prevention settings. Recent data suggest the plausibility of a dosage reduction while maintaining the biologic activity and minimizing the toxicity associated with tamoxifen.
Tamoxifen is an extremely well tolerated drug, and only rarely will it have to be discontinued because of toxicity. Its most common side-effect is hot-flashes, which are tolerated well by most patients. Other side effects include nausea, vomiting, weight gain, and vaginal bleeding or discharge. Occasionally patients complain of non-specific neurologic symptoms; thromboembolic disease; and visual disturbances caused by optic neuritis, retinopathy, and macular edema. Rarely patients with metastatic bone disease report increase in bone pain (tumor flare), with or without hypercalcemia within 1 to 2 weeks of initiating tamoxifen therapy. This phenomenon is believed to be related to tamoxifen's mild estrogenic effect, and it should be treated with supportive measures including analgesics and possibly low-dose prednisone. These symptoms usually dissipate within a few weeks, so tamoxifen should not be discontinued.
Reducing the risk for breast cancer recurrence after completion of tamoxifen treatment in postmenopausal women; in postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA-17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (e.g., letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer (8). The MA-17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence (P < 0.001). Following the publication of the final analysis, several other MA-17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported. Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial (8).
In women with ductal carcinoma in situ (DCIS) treated with complete local excision, radiotherapy reduces by about 60% to 70% new breast events of ipsilateral invasive and DCIS natures compared with no radiotherapy. In addition, contrary to initial findings, tamoxifen reduces by 30% the incidence of all new breast events as well as recurrent ipsilateral DCIS, and reduces contralateral tumors by about 55%. The conclusions come from an updated analysis presenting the long-term results of the UK/ANZ (United Kingdom, Australia, and New Zealand) DCIS trial (20). While the effect of radiotherapy was similar in this study, whether or not women received tamoxifen, the tamoxifen effect appeared only in women who did not receive radiotherapy.
Toremifene (Fareston) or chloro-tamoxifen is approved by FDA for treatment of metastatic breast cancer in postmenopausal women. Although toremifene exhibits antiestrogenic effects on the vaginal mucosa of estrogen-primed women, it has no effect in blocking short-term estrogen action in the uterus. Toremifene and tamoxifen produce the same estrogen-like effects on the histology of the postmenopausal endometrium; however no reliable long-term follow-up data are available on the incidence of endometrial cancer during toremifene treatment. Response rates, median time to disease progression, overall survival, and toxicity were similar between patients treated with the two drugs.
Other Tamoxifen-like Antiestrogens
Both droloxifene and idoxifene differ modestly in structure from tamoxifen. Both drugs appeared promising in laboratory experiments and small clinical trials evaluating their activity in patients with metastatic breast cancer (response rate up to 30%). Another drug in early development is lasofoxifene, a derivative of tetrahydronaphthalene. Animal experiments suggest that lasofoxifene maintains bone density and that development may be targeted toward prevention of osteoporosis and chemoprevention.
Selective Estrogen Receptor Modulators (SERMs)
The newer selective estrogen receptor modulators (SERMs) in development appear to possess potent antiestrogenic effects in the breast and uterus while retaining an agonist effect in bone. The most studied agent in this group is raloxifene (Evista).
Raloxifene (Evista) is an antiestrogen in the immature rate uterine weight test but has little agonist action on the uterus when administered alone. Raloxifene maintains bone density and tends to reduce circulating cholesterol. There is no evidence that raloxifene causes the formation of DNA adducts or induces hepato-carcinogenesis. The drug was subsequently developed and approved by the FDA for the treatment of osteoporosis (9). The Multiple Outcomes of Raloxifene Evaluation (MORE) trial randomized data revealed that there is a 70% reduction in breast cancer incidence in the raloxifene-treated patients, compared with those treated with placebo at 2 years and 54% reduction at 3 years (14). The rate of response in estrogen-receptor-positive breast cancer is better. The MORE trial (9) investigated the effects of the SERM raloxifene in postmenopausal women with osteoporosis. Patients were randomized to raloxifene 60 mg or 120 mg, or placebo. The primary endpoint was incidence of bone fractures and secondary endpoints were incidence of breast cancer and heart disease. A significant reduction in bone fractures led to FDA approval of raloxifene for the treatment of osteoporosis in postmenopausal women. The Continuing Outcomes Relevant To Evista (CORE) study (10) was an extension of the MORE study. All patients in CORE who had previously received raloxifene were assigned to raloxifene 60 mg, and placebo-treated patients continued on placebo. Patients were evaluated after receiving raloxifene for 8 years. Long-term raloxifene treatment reduced risk for overall breast cancer, invasive cancer, and ER positive breast cancer. Importantly, this agent is only approved for women with osteoporosis, and there has been minimal study in premenopausal women.
The Study of Tamoxifen and Raloxifene (STAR) trial was designed to determine the relative safety and efficacy of tamoxifen and raloxifene as preventive agents for breast cancer (11). In this trial, 19,747 postmenopausal women with a Gail risk >1.7 were randomized to oral tamoxifen 20 mg or raloxifene 60 mg for 5 years (11). Raloxifene was found to be as effective as tamoxifen in reducing invasive breast cancer incidence and demonstrated an improved safety profile. However, the rate of non-invasive breast cancer (ductal carcinoma in-situ, lobular carcinoma in-situ) was less in the tamoxifen arm; barely missing statistically significance. Raloxifene was also associated with significant decreases in the risk of uterine hyperplasia, hysterectomy surgery, and cataract surgery during follow-up.
Arzoxifene is a benzothiophene analog that is a more potent inhibitor than tamoxifen or raloxifene in in-vitro and in-vivo models of breast cancer (12). Preclinical studies also confirm that arzoxifene has greater agonist activity on bone and cholesterol metabolism compared with raloxifene and appears to have the added advantage of a lack of estrogen-like effect on uterine tissue. An ongoing randomized, phase 3 trial is comparing arzoxifene (20 mg/ day) with tamoxifen as first-line therapy of hormone-sensitive, metastatic breast cancer.
Luteinizing Hormone-Releasing Hormone (LHRH) Agonists
The primary effectiveness of luteinizing hormone-releasing hormone (LHRH) agonists for the treatment of breast cancer is to produce a reversible chemical castration. Naturally occurring LHRH is decapeptide with a short biologic half-life that is secreted in pulsatile fashion from hypothalamus into the portal circulation. LHRH causes the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary, which in turn stimulates the ovaries to synthesize and secrete estrogen. Of many LHRH agonists that have been synthesized, buserelin, leuprolide (Lupron) and goserelin (Zolodex) have been most extensively studied in clinical trials. All of these agents can be administered in a subcutaneous preparation, but buserelin and leuprolide are available in a depot preparation requiring a single monthly or every-3-month intramuscular injection. Goserelin is approved by the FDA for the treatment of breast cancer in premenopausal women. Other treatment strategies have attempted to provide maximal estrogen blockage by combining the use of tamoxifen and LHRH agonists.
Additive Hormonal Therapies
With the exception of progestins, other additive hormone therapies are rarely used in practice today, primarily because other forms of endocrine therapy are more effective and are associated with fewer side effects.
Megestrol acetate (Megace) and medroxyprogestrone acetate are the progestins most widely used to treat advanced breast cancer. They are associated with response rates similar to those of other hormonal treatments. Progestins have several mechanisms of action that might explain the observed antitumor effect in breast cancer patients. Treatment with progestins down-regulate the expression of the ER (and the PR), potentially making the cell less sensitive to the effects of estrogen. Megace is an orally active progesterone derivative with better gastrointestinal absorption and bioavailability than medroxyprogestrone acetate. Standard-dose megestrol acetate (160 mg/ day) administered orally results in blood levels 5 to 10 times higher than those detected in patients treated with 1000 mg of oral medroxyprogestrone acetate.
Treatment with high-dose estrogens such as diethylstilbestrol (DES) and ethinyl estradiol is effective as a therapy for advanced breast cancer and palliative care. The mechanism of action for estrogen's antitumor effect is unknown. High-dose DES (15 mg/day) produces beneficial effects in patients with the estrogen-receptor (ER)-positive breast cancer, possibly by down-regulating the ER and thereby decreasing the effect of estrogen. High-dose estrogen therapy is associated with toxicities, including vaginal bleeding, breast tenderness, cholestatic jaundice, nausea, vomiting and depression. Treatment with estrogen is accompanied by flare in about 10% of patients and withdrawal response after subsequent relapse in about 5% of patients.
Androgenic agents such as testosterone, fluoxymesterone, testolactone, and caluserone have been used to treat postmenopausal women with hormone-responsive breast cancer. Patients with ER-positive breast tumors respond better than those with ER-negative tumors. The mechanism of action of androgens is unknown but probably involves blocking the stimulating effect of estrogen. The high-incidence of androgenic side effects (e.g., hirsutism, male-pattern baldness, acne, fluid retention) makes these compounds second-line agents in the treatment of breast cancer. In addition, tumor may flare and hypercalcemia occurs more commonly with androgens than with other hormonal therapies. Danazol is a weak androgen that is associated with milder side effects compared with other androgens.
Aromatase Inhibitors (AIs)
The use of the newest generation of selective AIs has dramatically altered the endocrine treatment options for premenopausal patients with hormone receptor-positive breast cancer. Unlike its predecessors, the new-generation AIs are more potent and have far fewer adverse effects because of their selectivity for the aromatase enzyme without significant perturbing the aldosterone or cortisol synthesis pathways. Most widely used AIs are: anastrozole, letrozole, and exemestane. One of the important advantages of the new generation of AIs, over older non-selective AIs such as amino-glutethimide, is their selectivity for the aromatase enzyme without significantly perturbing the aldosterone or cortisol pathway. AIs also target ER. Clinical trials have suggested that AIs are superior to tamoxifen for the treatment of metastatic breast cancer in postmenopausal women, for adjuvant breast cancer, and for prevention of contralateral cancer. Notably, AIs do not increase the risk of thromboembolic disease, but may increase osteoporosis risk (13).
Hormonal Therapies for Early Breast Cancer
To establish the clinical and cost-effectiveness of aromatase inhibitors (AIs) anastrozole, letrozole and exemestane compared with tamoxifen in the adjuvant treatment of early estrogen receptor-positive breast cancer in postmenopausal women this meta-analysis of three trials (15) found a significant difference in overall survival when an unplanned anastrozole switching strategy was compared with 5 years' tamoxifen. Significant improvements in overall survival are yet to be demonstrated in other strategies. Compared with 5 years' tamoxifen, disease-free survival (disease recurrence or death from any cause) was significantly improved in the primary adjuvant setting with anastrozole and letrozole, and with an exemestane switching strategy. Other trials did not report this outcome. Breast cancer recurrence (censoring death as an event) was significantly improved with primary adjuvant anastrozole and letrozole, anastrozole switching, extended adjuvant anastrozole or letrozole. The AIs and tamoxifen have different side-effect profiles, with tamoxifen responsible for small but statistically significant increases in endometrial cancer and, sometimes, thromboembolic events and stroke. AIs show a trend towards increases in osteoporosis, the statistical significance of which increases with follow-up time. The absence of tamoxifen treatment also increases the risk of hypercholesterolemia and cardiac events in postmenopausal women. There was no significant difference in overall health-related quality of life between standard treatment and either primary adjuvant anastrozole and extended adjuvant letrozole strategies. The cost-effectiveness results for AIs compared with tamoxifen in the primary adjuvant setting are estimated to be between 21,000 pounds and 32,000 pounds per quality-adjusted life-year (QALY) based on an analysis over 35 years. There is currently no trial evidence for exemestane in this setting. The cost-effectiveness results for anastrozole and exemestane, compared with tamoxifen in the unplanned switching setting, are estimated to be 23,200 pounds and 19,200 pounds per QALY, respectively, based on an analysis over 35 years. There is currently no trial evidence for letrozole in this setting. In the extended adjuvant setting, the cost per QALY for letrozole compared with placebo is estimated to be 9800 pounds, based on an analysis over 35 years. All these results are considered to be conservative. In the base case it is assumed that the benefits of AIs over tamoxifen or placebo seen during the therapy period are gradually lost during the following 10 years. An alternative scenario, the 'benefits maintained' scenario, is tested in sensitivity analysis. Here it is assumed that following the treatment period the annual rate of recurrence in both arms is the same. This reduces the cost-effectiveness ratio by over 50%, to around 10,000-12,000 pounds, 5000 pounds and 3000 pounds in the primary adjuvant, unplanned switching and extended adjuvant setting, respectively. The limited evidence to date of benefits after the therapy period suggests that the 'benefits maintained' scenario may be realistic. The results from the economic analyses within the industry submissions are generally lower than the results from the authors' model and are close to or below 12,000 pounds in all three settings. The authors' analyses generally produce a lower estimate of QALY gain for the aromatase inhibitors, due to the more conservative assumption regarding benefits, along with differences in the utility values used in the their analysis.
On the basis of the current data and within their licensed indications, AIs can be considered clinically effective compared with standard tamoxifen treatment. However, their long-term effects, in terms of both benefits and harms, remain unclear. Under the conservative assumption that benefits gained by AIs during the treatment period are gradually lost over the following 10 years, the cost per QALY for AIs compared with tamoxifen is estimated to be between 21,000 pounds and 32,000 pounds in the primary adjuvant setting and around 20,000 pounds in the unplanned switch setting. The cost per QALY for AIs compared with placebo in the extended adjuvant setting is estimated to be around 10,000 pounds. Under the less conservative assumption that rates of recurrence are the same in both arms after the therapy period is complete, the incremental cost-effectiveness ratios are typically at least 50% lower, suggesting that AIs are likely to be considered cost-effective in all three settings. Understanding of the long-term treatment effects on cost-effectiveness is, however, incomplete. Data on the impact of AIs on survival are awaited from the majority of the trials to confirm whether or not the benefits seen in disease-free survival and recurrence rates are translated into overall survival benefit in the medium to long-term.
Tamoxifen, a medication used in the treatment of breast cancer, often induces menopausal symptoms. Certain medications and natural supplements taken or prescribed to alleviate tamoxifen-induced hot flashes and depressive states in women with breast cancer interact with tamoxifen. This paper (17) reviews potentially problematic interactions and offers treatment recommendations. Venlafaxine is efficacious for the treatment of hot flashes and depression and safe to use in combination with tamoxifen. Gabapentin is also efficacious in treating tamoxifen-induced hot flashes and, since it does not interact with cytochrome P450 system, is likely safe to use in patients using tamoxifen. Desvenlafaxine and pregabalin may be alternatives to venlafaxine and gabapentin, respectively, although desvenlafaxine has not yet been studied in this population. Paroxetine, fluoxetine and bupropion are strong CYP2D6 inhibitors which should be avoided in tamoxifen users. Fluvoxamine and nefazodone both inhibit CYP3A, which could potentially affect the metabolism of tamoxifen. Clonidine can be an alternative agent but may carry significant side effects. Evidence of medicinal products for the treatment of tamoxifen-induced hot flashes is equivocal at best (17). Clinicians should remain cautious about using strong inhibitors and/or inducers of cytochrome 2D6 and 3A4 concomitantly with tamoxifen. Use of natural menopausal supplements and diets rich in isoflavones should not be encouraged in tamoxifen users until more data is available. There are however safe treatments for hot flashes and depression in tamoxifen users.
Overview of Resistance to Systemic Therapy in Patients with Breast Cancer
Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002; 209,995 new cases of breast cancer were registered, and 42,913 patients died of it. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States (16). Worldwide, the problem is just as significant, as breast cancer is the most frequent cancer after non-melanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years. Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. In this review (12) general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions is discussed. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer will have recurrent disease, which is metastatic in most cases.
The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors. A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack of a response to a specific treatment. The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the American Joint Committee on Cancer (AJCC) staging system. The sixth edition of the AJCC staging system allows better prediction of prognosis by stage. However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion.
Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer (12). Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events. Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents. The pathological response to neoadjuvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a non-cross-resistant agent such as a taxane (14). In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65% (14).
Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation. Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy. The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months. In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower.
Genomic Testing and Chemotherapy Selection
The use of taxanes to treat node-positive (N+) breast cancer patients is associated with heterogeneous benefits as well as with morbidity and financial costs. This study (19) was aimed to assess the economic impact of using gene expression profiling to guide decision-making about chemotherapy, and to discuss the coverage/reimbursement issues involved. Retrospective data on 246 patients included in a randomized trial (PACS01) were analyzed. Tumors were genotyped using DNA microarrays (189-gene signature), and patients were classified depending on whether or not they were likely to benefit from chemotherapy regimens without taxanes. Standard anthracyclines plus taxane chemotherapy (strategy AT) was compared with the innovative strategy based on genomic testing (GEN). Statistical analyses involved bootstrap methods and sensitivity analyses. The AT and GEN strategies yielded similar 5-year metastasis-free survival rates. In comparison with AT, GEN was cost-effective when genomic testing costs were less than 2,090 euro. With genomic testing costs higher than 2,919 euro, AT was cost-effective. Considering a 30% decrease in the price of docetaxel (the patent rights being about to expire), GEN was cost-effective if the cost of genomic testing was in the 0 euro to 1,139 euro range; whereas AT was cost-effective if genomic testing costs were higher than 1,891euro. The use of gene expression profiling to guide decision-making about chemotherapy for N+ breast cancer patients is potentially cost-effective (19). Since genomic testing and the drugs targeted in these tests yield greater well-being than the sum of those resulting from separate use, questions arise about how to deal with extra well-being in decision-making about coverage/reimbursement.
HER2-Positive Breast Cancer
The HER2 gene encodes a tyrosine kinase receptor that mediates critical signaling functions in normal and malignant breast epithelial cells (21). An acquired alteration consisting of amplification and overexpression of the gene product occurs in approximately 20 to 25% of human breast cancers (22). HER2 overexpression is associated with an aggressive clinical phenotype that includes high-grade tumors, increased growth rates, early systemic metastasis, and decreased rates of disease-free and overall survival. Preclinical data indicate that this adverse clinical picture results from fundamental changes in the biologic features of breast-cancer cells containing the alteration, including increased proliferation, suppression of apoptosis, increased motility, greater invasive and metastatic potential, accelerated angiogenesis, and steroid hormone independence (22). An improved understanding of the molecular basis of malignant disease is allowing the development of rational treatment strategies that are more effective and less toxic than traditional empiric regimens. In previous studies, many of these HER2-medicated adverse characteristics were reversed by the use of monoclonal antibodies directed against the tyrosine kinase receptor, and these data led to phase 1 testing of a murine anti-HER2 monoclonal antibody, 4D5. Preliminary efficacy and safety data prompted the development of a humanized monoclonal antibody to produce trastuzumab (Herceptin). Alone and in combination with chemotherapy, trastuzumab has been shown to have an acceptable safety record and to be active in advanced HER2-positive disease (23). Subsequently, in a large randomized study, the addition of trastuzumab to chemotherapy yielded significant improvements in rates of objective response, response duration, and time to disease progression (56%, 58%, and 65% improvement, respectively), as well as 30% improvement in the rate of overall survival among patients with first-line metastatic disease (24). A significant side effect was an increase by a factor of 4 in the rate of cardiac dysfunction, including congestive heart failure, especially when trastuzumab was used in combination with anthracycline-based regimens (24).
These data led to the initial regulatory approval of trastuzumab for metastatic HER2-positive breast cancer and resulted in its evaluation in early-stage disease. Five randomized trials (four large and one small) were then launched to evaluated efficacy and safety of adjuvant therapy with trastuzumab, and findings in three of these trials have been reported (25). All showed a significant benefit of trastuzumab, with a reduction in the rate of recurrence of approximately 50% and improvement in the rate of survival approximately 30% (25). An increase by a factor of 4 to 5 in the rate of congestive heart failure was noted when trastuzumab was used with anthracyclines, and an even larger proportion of patients had subclinical loss of left ventricular function. Phase 2 and 3 trials of trastuzumab in patients with advanced disease showed that this regimen resulted in the longest period of progression-free survival reported to date, with rare cardiac dysfunction. In this study (26), the addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the non-anthracycline trastuzumab regimen over doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T) plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardio-toxicity and leukemia.
A test that measures the number of copies of the HER2 gene in breast tumor tissue has been approved by the U.S. Food and Drug Administration. If the Inform Dual ISH test is positive, then the patient is a candidate for treatment with trastuzumab, the recombinant monoclonal antibody directed against HER2 that is marketed as Herceptin by Genentech for the treatment of HER2 overexpressing breast cancer. The test is manufactured by Tucson, Ariz.-based Ventana Medical Systems, a member of the Roche group, as is Genentech. The test makes it possible to see and count copies of chromosome 17 and HER2 genes on the same slide, similar to HER2 amplification measurements that have traditionally only been available using fluorescence microscopes. The test confirms that the tumor sample contained more than the normal number of copies of the HER2 gene, located on chromosome 17, in 96% of the HER2 positive samples, in the study conducted in the United Sates that evaluated 510 women with breast cancer (27). This test allows lab staff to see the HER2 and chromosome 17 signals directly under a microscope, for longer periods of time. When used with other clinical information and laboratory tests, this test can provide health care professionals with additional insight on treatment decisions for patients with breast cancer.
Endocrine therapy has been used for the treatment of breast cancer for more than a century, but only in recent decades has a mechanistic model of hormonal influence on the development of progression of breast cancer been defined. Multiple forms of hormonal therapy have been evaluated, from surgical ablative techniques to modern pharmacologic approaches that use a rational drug design in an effort to block the influence of estrogen on tumor growth. The number of endocrine therapy options for patients with advanced disease has expanded, and the objective of several ongoing clinical trials is an effort to determine the optimal sequence of endocrine therapy. Tamoxifen is currently the standard preventive therapy for ER positive breast cancer in both pre- and postmenopausal women with a high Gail risk. Raloxifene has FDA approval for the treatment of osteoporosis, but its observed prevention of ER positivity has led to further study. The STAR trial has demonstrated raloxifene's efficacy and safety in postmenopausal women. However, many women at high risk of breast cancer will refuse preventive SERM therapy because of toxicity. Clinical trials have suggested that AIs are more effective preventive agents than SERMs with an improved side effect profile. AIs are being tested in several ongoing trials in postmenopausal women, which should provide important efficacy and safety information. Ultimately, the aim of current research is to develop breast cancer prevention regimens that are effective for both ER positive and ER negative cancers and have favorable side effect profiles. The identification and characterization of the HER2 alteration in a subset of human breast cancers and the subsequent development of trastuzumab (Herceptin) represent the practical realization of this translational ideal. The studies show that we can further exploit this new translational knowledge to optimize efficacy while simultaneously minimizing acute and chronic toxic effects in the adjuvant treatment of HER2-positive breast cancer.
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