Use of adjuvant herceptin in the treatment of HER2 positive breast cancer : what a healthcare provider needs to know

Transcription

1 The University of Toledo The University of Toledo Digital Repository Master s and Doctoral Projects 2007 Use of adjuvant herceptin in the treatment of HER2 positive breast cancer : what a healthcare provider needs to know Megan Marie Peck The University of Toledo Follow this and additional works at: Recommended Citation Peck, Megan Marie, "Use of adjuvant herceptin in the treatment of HER2 positive breast cancer : what a healthcare provider needs to know" (2007). Master s and Doctoral Projects. Paper This Scholarly Project is brought to you for free and open access by The University of Toledo Digital Repository. It has been accepted for inclusion in Master s and Doctoral Projects by an authorized administrator of The University of Toledo Digital Repository. For more information, please see the repository's About page.

2 Use of Adjuvant Herceptin in the Treatment of HER2 Positive Breast Cancer: What a Healthcare Provider Needs to Know Megan Marie Peck University of Toledo 2007

3 ii Acknowledgements I would like to thank both Dr. James Hampton and Dr. Brenda McGadney-Douglass for their help on this research project.

4 iii Table of Contents Introduction...1 Discussion...2 HER-2/neu Proto-oncogene...2 Detecting HER-2/neu Status...4 Herceptin Mechanisms...7 Side Effects...9 Herceptin Adjuvant (HERA) Trial...12 NSABP B-31 and NCCTG N Breast Cancer International Research Group 006 (BCIRG 006)...19 Finland Herceptin Study...21 Conclusion...23 Abstract...25 References...26

5 1 Introduction Worldwide, breast cancer is the most commonly seen cancer in women and will cause over 410,000 deaths this year (World Health Organization, 2005; Braga, dal Lago, Bernard, Cardoso, & Piccart, 2006). In the United States alone, about 212,920 women will be diagnosed with breast cancer and approximately 40,970 women will succumb to the disease (American Cancer Society, 2006, September 26). In addition, metastatic disease will eventually develop in about half of women diagnosed with breast cancer (Braga et al.). New treatment options for breast cancer such as radioactive pellets known as brachytherapy and anti-angiogenesis drugs like bevacizumab are constantly being developed (American Cancer Society, 2007, September 13). However, one of the newest treatments for breast cancer is a biological therapy known as Herceptin (trastuzumab). Herceptin is a humanized monoclonal antibody which binds with a high affinity to the extracellular domain of the HER-2 receptor (Plosker & Keam, 2006). Herceptin was approved by the FDA in September 1998 for use with paclitaxel (Taxol) as a first line treatment for HER-2 overexpressing metastatic breast cancer. Monotherapy Herceptin is approved for certain breast cancer patients unsuccessful on prior chemotherapy (Food and Drug Administration, 1998, September 25). Most recently, in November 2006, FDA approval was granted for the use of Herceptin in combination with other chemotherapeutic agents for the adjuvant treatment, treatment after surgery, of HER-2 positive breast cancer (Food and Drug Administration, 2006, November 16). References were obtained via the Internet using the search engine PubMed and the search terms Herceptin, trastuzumab, and trastuzumab and breast cancer.

6 2 Additional articles were obtained by searching the references of articles available on PubMed. Discussion HER-2/neu Proto-oncogene Proto-oncogenes are normal genes which by some type of DNA alteration or mutation become oncogenes, or tumor inducing genes (Huang et al., 2000). The HER- 2/neu proto-oncogene is located on chromosome 17 and encodes the HER-2 receptor (D. J. Slamon et al., 1987). This receptor belongs to an epidermal growth factor receptor family which also includes the homologous HER-1, HER-3, and HER-4 receptors. All members of the HER receptor family contain an intracellular domain, transmembrane domain, and extracellular domain and are found on the cell membrane in a variety of tissues. In addition, all HER receptors except HER-3 display intrinsic tyrosine kinase activity (Karamouzis, Badra, & Papavassiliou, 2007). The HER receptors exist as monomers and form receptor dimers upon ligand binding. These dimers can be either homodimers or heterodimers and are formed due to the higher stability of the ligand and two receptor complex compared to the receptor monomer. However, while ligands have been identified for HER-1, HER-3, and HER-4, no known ligand exists for HER-2. As a consequence, HER-2 acts mainly as a coreceptor for many different ligands, resulting in heterodimerization and leading HER-2 to be the preferred dimerization partner in the HER family. Indeed, HER-2 heterodimers have a higher potency compared to heterodimers and homodimers without HER-2. This high potency is due to prolonged ligand binding and decreased receptor internalization

7 3 and degradation seen with HER-2 heterodimers (Rubin & Yarden, 2001). Thus, HER-2 heterodimers have improved membrane stability and decreased degradation rates resulting in prolonged and enhanced HER-2 signaling (Karamouzis et al., 2007). The HER-2/neu gene and its encoded receptor are normal, as all breast epithelial cells contain HER-2 receptors, however, the pathogenic event is gene amplification and/or overexpression of the receptor (D. J. Slamon et al., 1989; Ross et al., 2003). Normally, the HER-2 receptor is responsible for cell proliferation and differentiation (Braga et al., 2006). These actions occur after activation of the HER-2 receptor by ligand binding and HER-2 dimerization with other HER family receptors (Ross et al.). With HER-2 overexpression, cell proliferation and differentiation are uncontrolled because receptor activation can occur independent of any ligand (Braga et al.). HER-2/neu amplification is the most frequently found oncogene amplification in breast tumors, occurring in 25 30% of tumors (Huang et al., 2000; D. J. Slamon et al., 1989). Amplifications of more than 2 to 20 times are seen in 30% of breast cancers (D. J. Slamon et al., 1987). These amplifications result in massive receptor overexpression, specifically, up to one million HER-2 receptors can be found per cell for a gene amplification of three to four times. About 90 95% of cases of HER-2 overexpression are directly due to gene amplification (Pauletti et al., 2000). Receptor overexpression without gene amplification is rare and occurs in less than 10% of breast cancer cases (Lebeau et al., 2001; D. J. Slamon et al., 1989). HER-2/neu gene amplification is not correlated with other prognostic factors such as tumor size, tumor grade, age at diagnosis, estrogen receptor status, or progesterone receptor status (Carr et al., 2000; D. J. Slamon et al., 1987). Because of this, HER-2

8 4 status is an independent predictor of disease prognosis (Carr et al.). Amplification of the HER-2/neu gene corresponds with a decreased time to disease recurrence and a diminished overall survival (D. J. Slamon et al., 1987). For example, one study found that patients with HER-2/neu gene amplification remained disease free for only 22 months compared to 40 months for those without gene amplification (Carr et al.). Detecting HER-2/neu Status HER-2/neu status is important to determine as it is a criteria for and also an indicator of responsiveness to Herceptin treatment. Two U.S. Food and Drug Administration (FDA) approved methods for detecting HER-2/neu status are fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) (Gonzalez- Angulo, Hortobagyi, & Esteva, 2006). FISH detects HER-2/neu gene amplification by measuring the numbers of genes per cell and amplification is often characterized as more than two genes per cell. IHC measures HER-2 protein expression using a subjectively graded scale of 0, 1+, 2+, or 3+ (Pauletti et al., 2000). HER-2 overexpression was previously characterized as IHC 2+ or 3+, while 0 or 1+ correlated to normal; however, in most current studies IHC 2+ now has a status of normal or indeterminate and only IHC 3+ is currently accepted as positive for HER-2 overexpression (Yeon & Pegram, 2005). IHC has an advantage over FISH in that IHC is more widely available, less costly, and allows easy analysis by a light microscope (Ross et al., 2003). However, IHC appears to lose sensitivity at lower HER-2/neu amplification levels due to standard fixation procedures which cause alterations in tissue sample antigens (Pauletti et al., 2000). In addition, IHC results are subjective which makes scoring difficult and possibly

9 5 variable between laboratories. Also IHC results are semi-quantitative, only telling if there is more or less receptor present and not giving an exact receptor number unlike the quantitative FISH results (Nahta & Esteva, 2006). FISH is ten times more costly than IHC and requires more technical skills, time, and a fluorescence microscope for interpretation (Jacobs, Gown, Yaziji, Barnes, & Schnitt, 1999). Despite these downfalls, FISH has superior sensitivity and specificity compared to IHC (Pauletti et al.). In fact, FISH, with sensitivities and specificities reported as high as 98% and 100% respectively, is considered by some to be the gold standard for detecting HER-2 status (Peiro et al., 2007). Both IHC and FISH can be used to predict decreased patient survival: IHC by a 3+ level protein overexpression and FISH by the presence of more than two HER-2/neu genes per cell. Protein overexpression (IHC positive) in the absence of gene amplification (FISH negative) is rare, but predicts an outcome similar to what would be seen in patients without any HER-2 alterations. However, gene amplification (FISH positive), without overexpression (IHC negative), predicts a poorer survival than the aforementioned overexpression without amplification. This suggests that FISH is more indicative of breast cancer prognosis and patient outcome compared to IHC (Pauletti et al., 2000). More importantly, patient responsiveness to Herceptin therapy is better predicted by FISH. As an example, the limited number of patients IHC positive for receptor overexpression and FISH negative for gene amplification rarely respond to Herceptin therapy (Nahta & Esteva, 2006). The concordance rates between IHC and FISH vary from 80 92% depending on the studies cited (Gonzalez-Angulo et al., 2006). Reported concordance rates can differ

10 6 based on whether only IHC 3+ or IHC 2+ and 3+ are classified as positive for HER-2 overexpression (Braga et al., 2006). One study found that all tumors with high gene amplification, greater than ten genes per cell, were positive for receptor overexpression when classifying both IHC 2+ and 3+ as positive. In contrast, among tumors found to be IHC 2+ by the HercepTest, an FDA approved IHC test kit, 75% were shown to be FISH negative (Lebeau et al., 2001). In the initial Herceptin trials, patients with HER-2 protein overexpression at the IHC 2+ level showed no significant benefit from Herceptin therapy (Pauletti et al., 2000). Thus, only a tumor with IHC 3+ protein overexpression and/or gene amplification as measured by FISH is considered clinically relevant with regards to Herceptin therapy (Braga et al., 2006). However, because there is a subset of patients who are both IHC 2+ and FISH positive, FISH should be used to confirm those IHC 2+ patients who are also FISH positive and may benefit from Herceptin therapy (Gonzalez-Angulo et al., 2006). Another method not yet FDA approved for detecting HER-2 status is chromogenic in situ hybridization (CISH). This method uses an immunoperoxidase reaction to detect HER-2 gene copies. CISH has several advantages over FISH: lower cost, evaluation with a standard light microscope, and easier test performance for technicians (Peiro et al., 2007). Additionally, CISH results, which show similarity to IHC, are easier to interpret for individuals not trained in fluorescence. However, the main disadvantage of CISH is the lack of a current standardized hybridization procedure for detecting HER-2 status (Arnould et al., 2003). CISH appears to have a relatively high correlation with both IHC and FISH. In a sample of 159 tumors, 147 tumors or 92.5% demonstrated concordance between IHC and

11 7 CISH results (Peiro et al., 2007). Another study found a 98% agreement between IHC and CISH when looking at IHC 0, 1+, and 3+ tumors, but the more indeterminate IHC 2+ tumors displayed only a 93% agreement with CISH. In comparison of CISH and FISH, a correlation was found in 96% or 72 of 75 tumors. Because of the aforementioned correlations and the relative ease of performing and interpreting CISH, this method may eventually be standardized and approved for and perhaps even replace other methods for the detection of HER-2 status (Arnould et al., 2003). Herceptin Mechanisms Herceptin is an immunoglobulin G1 type antibody which targets the extracellular domain of the HER-2 receptor. Because HER-2 is overexpressed in certain breast cancers compared to the expression in normal tissues, Herceptin preferentially targets cancer cells and therefore reduces toxicity to normal tissues. In addition, Herceptin therapy may be effective at not only primary but also metastatic sites, as both display HER-2 overexpression. The mechanisms by which Herceptin acts on HER-2 overexpressing tumors are not completely understood, although several Herceptin actions and effects have been experimentally observed (Valabrega, Montemurro, & Aglietta, 2007). Herceptin has been proposed to interact with the PI3 kinase (PI3K) and the MAP kinase (MAPK) signaling pathways. Cell proliferation is arrested and apoptosis occurs when Herceptin interferes with and reduces signaling from these pathways (Nahta & Esteva, 2006). However, it is uncertain whether this reduced signaling is due to Herceptin promoted HER-2 internalization and degradation, as at least one study has

12 8 found no HER-2 downregulation in patients treated with Herceptin. A study by Gennari et al found that patients who received four weeks of neoadjuvant Herceptin displayed no significant HER-2 receptor downregulation (Gennari et al., 2004). The inhibition of HER-2 extracellular domain cleavage is another suggested Herceptin mechanism. When the HER-2 receptor is overexpressed, the extracellular domain is cleaved and released into the serum (Nahta & Esteva, 2006). Herceptin therapy leads to a decrease in serum HER-2 extracellular domain, suggesting that Herceptin blocks HER-2 cleavage. Additionally, Herceptin has been found to inhibit metalloproteinase activity which is necessary for HER-2 extracellular domain proteolytic cleavage (Valabrega et al., 2007). HER-2 overexpression is associated with an increased expression of vascular endothelial growth factor (VEGF) and subsequent angiogenesis, or increased vascularization of tumors. Treatment with Herceptin upregulates the expression of antiangiogenic factors and downregulates the expression of VEGF and other pro-angiogenic factors, leading to a reduction in tumor vasculature. Thus, Herceptin works to decrease tumor volume by its anti-angiogenic properties, or its ability to rob the tumor of its blood supply (Yeon & Pegram, 2005). Another Herceptin mechanism is inhibition of the cell cycle during the G1 phase, leading to a reduction in tumor cell proliferation (Nahta & Esteva, 2006). Herceptin not only inhibits cell proliferation, but also contributes to a type of cell death known as antibody dependent cellular cytotoxicity. The Fc domain of the Herceptin antibody corresponds to the Fc receptor found on the surface of natural killer cells. Upon Fc

13 9 domain binding to its Fc receptor, the natural killer cell is activated which results in lysis of cancer cells bound to Herceptin (Valabrega et al., 2007). Herceptin is often used in combination with other chemotherapeutic agents, as Herceptin can inhibit the repair of DNA damage caused by those agents (Nahta & Esteva, 2006). A combination of Herceptin and cisplatin radiation therapy led to a 35 40% decrease in DNA repair after radiation exposure. Furthermore, in studies utilizing both Herceptin and radiation therapy, DNA synthesis decreased 25-44% in HER-2 overexpressing cells. The previous studies suggest that Herceptin, by inhibiting DNA repair and synthesis, can result in tumor cell death or apoptosis (Yeon & Pegram, 2005). Side Effects Herceptin has a number of side effects ranging from mild to potentially severe or life-threatening (Plosker & Keam, 2006). Infusion related reactions typically occur during the initial Herceptin infusion and rarely develop with subsequent infusions. These reactions can involve a constellation of symptoms including any of the following: fever, chills, nausea, vomiting, dizziness, headache, cough, pain, and rash. Occasionally, reactions to Herceptin can be severe and involve more of a hypersensitivity type reaction. Symptoms of such a reaction include hypotension, hypertension, wheezing, dyspnea, bronchospasm, respiratory distress, anaphylaxis, urticaria, and angioedema. Again, hypersensitivity reactions are more likely to occur with the initial Herceptin infusion, and if they develop, Herceptin infusion should be immediately discontinued (Plosker & Keam).

14 10 Cardiac dysfunction was an unexpected adverse event demonstrated in the initial Herceptin trials and is measured by left ventricular ejection fraction and the New York Heart Association (NYHA) functional classification system (Ewer et al., 2005). Herceptin as a single agent appears to cause cardiotoxicity in about 7% of patients, while Herceptin combined with an anthracycline causes at least mild cardiotoxicity in up to 27% of patients. Moreover, 16% of patients treated with the Herceptin and anthracycline combination in clinical trials developed more severe cardiotoxicity as manifested by NYHA class III or IV congestive heart failure. Therefore, concurrent use of Herceptin and an anthracycline is highly discouraged and should be avoided (Ewer et al.). In an evaluation of 173 patients receiving Herceptin therapy, many of whom had previous anthracycline therapy, 49 patients experienced a cardiac event (Guarneri et al., 2006). Nineteen patients experienced a left ventricular ejection fraction (LVEF) of 20-40% or symptoms of CHF, 27 patients experienced a LVEF of 40-50% without cardiac symptoms, and 3 patients experienced a LVEF reduction of 20% without symptoms. Most importantly, only 15 patients in the study were symptomatic, and of these symptomatic patients 12 recovered with cardiac therapy. The other three patients did not recover and one of these three subsequently died due to cardiac related events (Guarneri et al.). An evaluation of 1,219 patients in another study treated with Herceptin resulted in 110 patients developing cardiac dysfunction with 83 of these 110 patients being symptomatic. Seventy-nine percent of the symptomatic patients treated for CHF showed improvement (Perez & Rodeheffer, 2004). These results suggest that Herceptin induced cardiac dysfunction is reversible, especially with supportive medical treatment (Perez & Rodeheffer).

15 11 The exact pathogenesis of Herceptin related cardiotoxicity remains unclear; however, there are some areas of speculation. Initially, Herceptin was thought to have an inherent cardiotoxicity similar to anthracyclines, but the lack of findings on myocardial biopsy seems to differentiate Herceptin from anthracycline induced toxicity (Ewer et al., 2005). HER-2 appears to play a role in embryonic cardiogenesis and the HER-2 pathway is necessary for preventing dilated cardiomyopathy (Guarneri et al., 2006). Therefore, the Herceptin monoclonal antibodies can disrupt the HER-2 signaling pathway, potentially leading to left ventricular dysfunction (Ewer et al.). In order to truly optimize Herceptin therapy and minimize cardiotoxicity, factors identifying individuals at risk for cardiac sequelae need to be determined. One study shows that the risk of cardiac events is increased with a decreasing time span between anthracycline and Herceptin administration (Guarneri et al., 2006). Another study displayed an increasing risk of cardiac dysfunction with Herceptin plus both anthracycline and cyclophosphamide combination chemotherapy and increasing age (Perez & Rodeheffer, 2004). Additionally, suspected but unproven risk factors include pre-existing cardiac dysfunction and a cumulative anthracycline dose of > 400mg/m² (Keefe, 2002). However, no association was demonstrated between Herceptin mediated cardiotoxicity and factors such as prior radiotherapy and pre-existing hypertension. More research needs to be done to identify pre-existing risk factors predisposing individuals to Herceptin induced cardiotoxicity, so that these risk factors can potentially can be assessed and managed earlier in high risk patients, possibly preventing cardiac sequelae (Perez & Rodeheffer).

16 12 Another adverse effect associated with Herceptin treatment is an increased incidence of brain metastases. CNS involvement occurs in about 14-20% of metastatic breast cancer patients and 25-48% of breast cancer patients treated with Herceptin (Stemmler et al., 2006). There are two reasons postulated for the higher prevalence of CNS involvement with Herceptin therapy. First, Herceptin is unable to penetrate the blood brain barrier because of its high molecular weight (Duchnowska & Szczylik, 2005). Second, because brain metastases are a late finding in metastatic disease, Herceptin may be allowing patients to live long enough to manifest such findings (Stemmler et al.). Herceptin Adjuvant (HERA) Trial The HERA trial is a phase 3 randomized trial evaluating the adjuvant use of Herceptin in early-stage HER-2 positive breast cancer (Piccart-Gebhart et al., 2005). Patients involved in this trial were randomly assigned to one of three groups: adjuvant Herceptin for two years, adjuvant Herceptin for one year, or observation alone. Prior to being involved in this study, all patients had undergone surgery and completed at least four cycles of chemotherapy. Inclusion criteria for the HERA trial included a receptor overexpresson level of 3+ and gene amplification positive by FISH. Additionally, the four cycles of chemotherapy mentioned previously were completed before randomization in either the adjuvant period, neoadjuvant period, or both. Also, patients with either node positive or node negative disease were eligible for inclusion. Some exclusion criteria included a non-breast neoplasm, previous breast cancer, or distant metastases. In addition, patients

17 13 with a left ventricular ejection fraction (LVEF) of less than 55% were ineligible for the study. Other cardiac exclusion factors included uncontrolled hypertension, valvular disease, unstable arrhythmias, angina, coronary artery disease, and a history of congestive heart failure (CHF). After application of inclusion and exclusion criteria, 1,694 patients were assigned to the two year Herceptin group, 1,694 patients to the one year Herceptin group, and 1,693 patients to the observation group. Disease-free survival, as measured by the occurrence of any disease-free survival event, was the primary endpoint for the HERA trial. These events included: breast cancer recurrence at any site, contralateral or ipsilateral breast cancer development, development of a non-breast neoplasm, or death from any cause. Site of the disease free survival event, cardiac safety, overall survival, and time to disease recurrence were secondary endpoints. Because of significant improvements in disease-free survival with the Herceptin group at interim analysis, results for the one year Herceptin and the one year observation group were released early (Piccart-Gebhart et al., 2005). There were 220 disease-free survival events reported in the observation group compared to only 127 events in the Herceptin group. Hence, Herceptin decreased the occurrence of initial events by 46%. Distant disease recurrence occurred in 154 individuals in the observation group and 85 individuals in the Herceptin group, corresponding with a 51% decrease in distant recurrence with Herceptin therapy. Local breast cancer recurrence occurred in 17 or 1% of patients in the Herceptin group and 37 or 2.2% of patients in the observation group. Additionally, total deaths numbered 37 in the observation group compared to 29 in the

18 14 Herceptin group. The significance of these results is underscored by the fact that all patients in the observation group were given the option of starting Herceptin therapy. It was mentioned earlier that one of the more serious side effects of Herceptin therapy is cardiotoxicity and the HERA trial was no exception. Indeed, in the Herceptin group, 29 patients experienced symptomatic CHF and 113 patients had a decrease in LVEF of greater than or equal to ten percentage points, resulting in a LVEF of less than 50%. Those numbers are significantly higher than the one patient experiencing symptomatic CHF and 34 patients with a decrease in LVEF seen in the observation group. Also, 9 of the 29 patients experiencing CHF in the Herceptin group were classified as having severe CHF, NYHA class III or IV, as compared to no cases of severe CHF in the observation group. While the HERA trial does demonstrate cardiotoxicity, the cardiotoxicity is not as compelling as many other trials, specifically those mentioned under the side effects section (Ewer et al., 2005; Guarneri et al., 2006; Perez & Rodeheffer, 2004). This could be due to the fact that patients in the HERA trial had to meet certain cardiac criteria to be eligible, so perhaps patients with underlying cardiac disease were excluded from the trial. Additionally, in many previous Herceptin studies, Herceptin was only utilized in metatstatic breast cancer patients; hence, these patients may have been sicker and more susceptible to the cardiac effects of Herceptin. It remains to be seen whether cardiotoxicity will increase with two years of Herceptin use or with prolonged follow-up of patients involved in the HERA trial. While the results for the two year Herceptin treatment group have yet to be released, the importance of the overall HERA study design must be emphasized. The fact

19 15 that patients will be treated with up to two years of Herceptin therapy is crucial for several reasons. First, breast cancer relapse tends to peak months after surgery. Second, it is unknown how long Herceptin needs to be administered to effectively treat HER-2 positive breast cancer. Finally, a different but also effective type of targeted therapy for breast cancer, known as tamoxifen, has been shown in clinical trials to be most beneficial when administered for greater than one year (Piccart-Gebhart et al., 2005). The interim results of the HERA trial are compelling because they show that Herceptin can halve the rates of cancer recurrence. This trial proves that Herceptin can be effective not only in late stage metastatic disease, but also in early stage post-surgical breast cancer. Also, because patients involved in this trial had previously undergone chemotherapy with a variety of regimens, it appears that the effectiveness of Herceptin therapy is not dependent on prior chemotherapeutic regimens. Overall, the results of the HERA trial suggest that at least one year of adjuvant Herceptin therapy should be a standard of treatment for any patient who meets criteria similar to those used in this trial (Piccart-Gebhart et al., 2005). National Surgical Adjuvant Breast and Bowel Project trial B-31 (NSABP B-31) and North Central Cancer Treatment Group trial N9831 (NCCTG N9831) The National Surgical Adjuvant Breast and Bowel Project trial B-31 (NSABP B- 31) and the North Central Cancer Treatment Group trial N9831 (NCCTG N9831) are two clinical trials studying Herceptin use in the adjuvant setting (Romond et al., 2005). Two groups are compared in the Breast and Bowel Project (NSABP trial B-31): group 1

20 16 consists of patients receiving four cycles of doxorubicin and cyclophosphamide followed by paclitaxel, while group 2 follows the previous regimen but adds 52 weeks of Herceptin therapy beginning concurrently with paclitaxel. Three groups are compared in the Cancer Treatment Group (NCCTG trial N9831): group A involves four cycles of doxorubicin and cyclophosphamide followed by paclitaxel weekly for 12 weeks, patients in group B receive the previous regimen with 52 weeks of Herceptin after completing paclitaxel therapy, group C consists of four cycles of doxorubicin and cyclophosphamide followed by concurrent paclitaxel and 52 weeks of Herceptin therapy. Because these two studies are similar, a joint analysis was planned which compared combined results from group 1 and group A (control group) to group 2 and group C (Herceptin group). Inclusion criteria for the trials included IHC 3+ or FISH positive adenocarcinoma of the breast (Romond et al., 2005). Additionally, in the initial enrollment period, patients were required to have node positive disease. Patients were also required to have adequate renal and hepatic function and a LVEF at or above the lower limits of normal. The cardiac exclusion criteria included: angina pectoris or arrhythmia requiring medication, significant valvular disease, conduction abnormality, uncontrolled hypertension, cardiomegaly on chest radiograph, or a history of cardiomyopathy, CHF, or myocardial infarction. Specifically, in the Breast and Bowel Project, patients were excluded if they demonstrated left ventricular hypertrophy on cardiac echo. Also, patients in Cancer Treatment Group were ineligible if they had significant pericardial effusion. Patients with evidence of metastatic disease were excluded from either trial. The initial interim analysis was planned after the occurrence of 355 events and by March 2005, 394 events had occurred. Disease-free survival as determined by death,

21 17 contralateral breast cancer, and local, regional, or distant recurrence was the primary endpoint of both studies. Secondary endpoints included time to distant recurrence and overall survival. Because of the significance of the results, enrollment in both trials was stopped and the interim results were released. The number of patients available for follow-up included 1,679 patients in the control group (872 in group 1 and 807 in group A) and 1,672 patients in the Herceptin group (864 in group 2 and 808 in group C). Median follow-up for the combined analysis of the two trials was two years. In the control group, 261 events occurred compared to only 133 events in the Herceptin group, corresponding to a 52% reduction in first events with the use of Herceptin. Herceptin therapy was also associated with a 33% reduction in mortality, as there were only 62 deaths in the Herceptin group compared to 92 deaths in the control group. The risk of distant metastases, which occurred in 96 patients in the Herceptin group and 193 patients in the control group, was decreased by 53% with Herceptin therapy. Because of the nature of these trials and the fact that some patients started the protocol in 2000, a number of patients have data available at the three and four year marks. At three years after randomization, overall survival was 91.7% for the control group and 94.3% for the Herceptin group. Overall survival at four years was 86.6% for the control group and 91.4% for the Herceptin group. Disease-free survival at three years was 75.4% for the control group and 87.1% for the Herceptin group and at four years was 67.1% and 85.3%, respectively. As mentioned earlier, breast cancer patients seem to have an increased frequency of brain metastases with Herceptin treatment. In the Breast and Bowel Project (B-31), brain metastases were the first event in 21 patients on Herceptin therapy compared to 11

22 18 patients in the control group. In the Cancer Treatment Group (N9831), 12 patients on Herceptin therapy experienced brain metastases as a first event compared to only 4 patients in the control group. These results would seem to suggest that even in early stage breast cancer, Herceptin therapy is associated with a greater number of brain metastases. However, it is possible that in the control group earlier metastatic recurrence in other organs may have masked the incidence of brain metastases. Trial N9831 did not follow patients past the first event, but trial B-31 did and found that in the control group, brain metastases were a first or subsequent event in 35 patients compared to only 28 patients in the Herceptin group. Therefore, it appears that among patients in the control group, other earlier distant recurrences decrease the likelihood that brain metastases will be seen as a first event (Romond et al., 2005). Like other Herceptin trials, cardiotoxicity was present in both the Breast and Bowel Project (B-31) and Cancer Treatment Group (N9831) trials. After three years in trial B-31, 4.1% of patients in the Herceptin group and 0.8% of patients in the control group experienced either death from cardiac causes or NYHA class III or IV CHF. Thirty-one patients in the B-31 Herceptin group experienced CHF, and of these patients, 27 were followed for at least six months after developing CHF. Of these 27 patients, 26 fully recovered and only one continued to report residual CHF symptoms. Patients in the B-31 trial did experience modest declines in LVEF from a median baseline LVEF of 63%. After doxorubicin and cyclophosphamide therapy, the median decrease in LVEF was 2% with an additional decrease after paclitaxel and paclitaxel plus Herceptin therapy. In the paclitaxel plus Herceptin group, LVEF baseline values decreased 5%, 6%, and 4% at 6, 9, and 18 months, respectively. In the paclitaxel only group, LVEF declined 3%,

23 19 2%, and 3% from baseline at 6, 9, and 18 months, respectively. The B-31 trial was also able to identify possible risk factors for CHF, as both age at entry and baseline LVEF were strongly associated with, and hypertension was marginally associated with CHF (Tan-Chiu et al., 2005). For trial N9831, no patients in the control group and 2.9% of patients in the Herceptin group experienced NYHA class III or IV CHF or cardiac related death after three years (Romond et al., 2005). Again, these trials demonstrate a significant benefit with Herceptin in the adjuvant setting. Most importantly, the use of Herceptin in these trials cut cancer recurrence rates in half for women with HER-2 positive breast cancer. Additionally, the risk of mortality was reduced by one-third with Herceptin use. However, Herceptin in the adjuvant setting is not without risks as cardiotoxicity is one of the main adverse effects. Despite this fact, results of trial B-31 suggested that CHF is reversible with proper management and LVEF generally recovers with time (Tan-Chiu et al., 2005). The long-term impact of this cardiotoxicity, whether transient or not, on quality of life and overall survival remains to be seen and will require additional follow-up (Romond et al., 2005). Breast Cancer International Research Group 006 (BCIRG 006) The Breast Cancer International Research Group (BCIRG 006) study evaluated the use of adjuvant Herceptin in 3,222 patients with the goal of minimizing cardiac toxicity and maximizing efficacy. Three different regimens were studied: 1,073 patients received doxorubicin and cyclophosphamide followed by docetaxel (AC-T, control group), 1,074 patients received the above regimen with the addition of Herceptin administered with docetaxel (AC-TH), and 1,075 patients were administered concurrent

24 20 docetaxel, carboplatin, and Herceptin (TCH). In both regimens utilizing Herceptin therapy, Herceptin was administered for one year. Patients in this study had either lymph node positive or high risk lymph node negative HER-2 positive breast cancer as confirmed by FISH. Disease-free survival was the primary endpoint while secondary endpoints included cardiac toxicity and overall survival (D. Slamon, Eiermann, Robert, & et al., 2005). Cardiac toxicity was defined as arrythmias, ischemia/infarction, symptomatic CHF, asymptomatic LVEF decline, or cardiac death (Baselga, Perez, Pienkowski, & Bell, 2006). After a median follow-up of 23 months, the use of Herceptin resulted in a 51% decrease in disease recurrence in the AC-TH group and a 39% decrease in the TCH group. Thus far, the difference in disease recurrence between the two Herceptin groups is not statistically significant (D. Slamon et al., 2005). In the control group, 0.3% of patients experienced class III or IV CHF compared to 1.6% in the AC-TH and 0.4% in the TCH group (Baselga et al., 2006). Overall, any symptomatic cardiac event occurred in 1.2% of patients in the control group, 1.2% in the TCH group, and 2.3% in the AC-TH group (D. Slamon et al.). The results of this study suggest that Herceptin therapy is effective when used in the standard AC-TH regimen with anthracycline or without anthracycline in the TCH regimen (D. Slamon et al., 2005). Additionally, it is known that greater cardiotoxicity is observed when Herceptin is administered to patients with previous anthracycline exposure. Indeed, in this study fewer cardiac events were observed in the TCH group compared to the AC-TH group (D. Slamon et al., 2005). The effectiveness of and the lower cardiotoxicity associated with the TCH regimen suggest that perhaps this regimen

25 21 or other non-anthracycline based Herceptin containing regimens will become a treatment alternative for women with underlying cardiac disease or pre-existing cardiac risk factors (Baselga et al., 2006). Finland Herceptin Study (FinHer) The Finland Herceptin (FinHer) study looked at the treatment of adjuvant breast cancer with docetaxel or vinorelbine with or without Herceptin therapy (Joensuu et al., 2006). This study included 1,010 patients treated with either docetaxel followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC), or treated with vinorelbine followed by FEC. Of the 1,010 patients, 232 were HER-2 positive and these patients were assigned to the above regimens with (116 patients) or without (116 patients) Herceptin therapy. Herceptin was given on the first day of docetaxel or vinorelbine therapy and was given at one week intervals for a total of nine infusions. Inclusion criteria for the study included node positive or high risk node negative breast cancer and an age of less than 66 years. Exclusion factors included pregnancy, distant metastases, uncontrolled hypertension, and cardiac disease as manifested by symptoms of cardiac failure, arrhythmias managed by medication, or a myocardial infarction occurring within the previous 12 months. HER-2 status was determined by IHC, and any patient with an IHC of 2+ or 3+ was confirmed by CISH. Of the IHC 3+ cancers, 84.3% were CISH positive for HER-2/neu gene amplification, while only 26.2% of the IHC 2+ cancers displayed HER-2/neu amplification. Disease-free survival was the primary endpoint and was determined by local, distant, or contralateral breast cancer

26 22 recurrence, or death. Overall survival, time to recurrence, changes in LVEF, and adverse effects were secondary endpoints. After a median follow-up time of 35 to 37 months, 12 patients in the Herceptin group experienced breast cancer recurrence or death compared to 27 patients in the control group (women with HER-2 positive breast cancer not receiving Herceptin therapy). This corresponds to a 58% decrease in the risk of cancer recurrence or death with Herceptin therapy. Eight distant recurrences occurred in the Herceptin group compared to 26 in the control group corresponding to a 71% reduction in distant disease recurrence with Herceptin therapy. Additionally, Herceptin was associated with a 59% decrease in death, as only six patients taking Herceptin died compared to 14 in the control group. Surprisingly, the cardiac toxicity observed in other Herceptin trials was not seen in the FinHer trial. In fact, LVEF was preserved and even slightly higher in patients using Herceptin compared to the control group. This maintenance of LVEF and cardiac function may be due to the fact that Herceptin was administered prior to any radiotherapy or the FEC chemotherapy regimen. This trial again demonstrates the significant outcomes seen with Herceptin in the adjuvant setting. These outcomes include a significant risk in disease recurrence including distant recurrence and a decreased risk of mortality. However, there are some limitations to this trial, including the small sample size, the short duration of follow-up, and the short duration of Herceptin therapy. Nevertheless, the results obtained in this trial are similar to those seen in the larger trials (Joensuu et al., 2006).

27 23 Conclusion Herceptin is one of the newer weapons in the arsenal against breast cancer. Unlike typical chemotherapy regimens, Herceptin is a monoclonal antibody which binds to the HER-2 receptor and is only effective against a subset of breast cancers with HER-2 receptor overexpression. In order for Herceptin therapy to be useful, HER-2 status must be assessed and measured positive by IHC, FISH, or CISH. Most importantly, breast cancers with HER-2 overexpression are aggressive and associated with a decreased overall survival and a decreased time to disease recurrence, hence, Herceptin offers hope to patients with an otherwise dismal prognosis (Plosker & Keam, 2006). While Herceptin was initially FDA approved for use in metastatic breast cancer, it was only recently approved for early stage adjuvant breast cancer (Food and Drug Administration, 2006, November 16). The several trials evaluating Herceptin in the adjuvant setting demonstrated astounding results. Specifically, the risk of distant disease recurrence was decreased by 51% in the HERA trial and up to 71% in the FinHer trial. Additionally, Herceptin therapy was associated with a decreased risk of mortality from 24% in the HERA trial to 59% in the FinHer trial. The main and most important side effect of Herceptin therapy is cardiac toxicity which occurred to variable degrees in each trial except FinHer (Joensuu et al., 2006; Piccart-Gebhart et al., 2005). This suggests a need to carefully select patients for Herceptin therapy in order to minimize adverse cardiac effects (Gonzalez-Angulo et al., 2006). Moreover, patients being treated with Herceptin need to have regular monitoring of cardiac function (Baselga et al., 2006).

28 24 It is important for any healthcare provider, including physician assistants (PAs), to be familiar with the information contained in this article. PAs working in any field need to have a basic understanding of general topics including breast cancer and its treatment options. Some PAs, especially those in oncology, may need to counsel patients with breast cancer about HER-2 positive breast cancer, its prognosis, and the benefits and risks of Herceptin therapy. However, PAs in any practice may encounter breast cancer survivors and may need to understand the type of therapy these patients received in order to understand possible long term side effects of therapy.

29 25 Abstract Objective: Herceptin is an important weapon in the fight against HER-2 positive breast cancer. However, the significant effects of this biological therapy in the adjuvant setting have only recently been demonstrated in multiple trials. Methods: References were obtained via the Internet using the search engine PubMed and the search terms Herceptin, trastuzumab, and trastuzumab and breast cancer. Additional articles were obtained by searching the references of articles available on PubMed. Results: The results of several trials confirm the effectiveness of, and support the FDA s approval of Herceptin therapy for HER-2 adjuvant breast cancer. In multiple trials, adjuvant Herceptin was found to decrease the risk of cancer recurrence by 51% to 71%. Additionally, adjuvant Herceptin has been shown to result in a 24% to 59% decrease in overall mortality in breast cancer patients. However, Herceptin therapy is not without side effects, the most severe being cardiotoxicity, which is mostly reversible by terminating Herceptin therapy. Conclusion: Adjuvant Herceptin therapy for HER-2 positive breast cancer provides an effective therapeutic option for patients with an otherwise aggressive form of breast cancer.

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