Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. O'Regan and and McCune. This program is available as read only, with accompanying audio, and accredited articles in PDF foramt.
*Scroll to read lecture and/or follow along with audio.
Slide 1: Welcome to the teleconference, Diagnosis and Management of HER2-Positive Breast Cancer: Opportunities to Improve Patient Outcomes. This program is jointly sponsored by the Medical Education Collaborative, Inc and Princeton CME, and is supported by an educational grant from Genentech BioOncology.
This educational activity is designed to educate the target audience of managed markets physicians and pharmacists, case managers, and practice managers on practical, evidence-based approaches to improve patient outcomes in HER2-positive breast cancer
Slide 2: After completing this activity, participants should be able to:
- Describe the clinical and economic burden of HER2-positive breast cancer and the impact of early classification and management
- Outline current and emerging diagnostic measures for breast cancer identification and classification
- Summarize the risk/benefit profiles of HER2-positive breast cancer medications, including chemotherapeutic and biologic therapies; and
- Discuss evidence-based approaches to HER2-positive breast cancer diagnosis and management to optimize patient outcomes
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medical Education Collaborative, Inc (MEC) and Princeton CME. MEC is accredited by the ACCME to provide continuing medical education for physicians.
MEC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
For questions regarding the ACCME accreditation of this activity, please contact MEC at 866-420-3252.
Princeton CME is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (ACPE Provider #452) and complies with the Criteria for Quality and Interpretive Guidelines. This activity is approved for 1 contact hour, or 0.1 CEU, of continuing pharmacy education. The Universal Program Number for this activity is 452-999-08-012-H01-P.
This activity is approved for 1 hour of continuing education credit for case managers by the Commission for Case Manager Certification (CCMC).
Faculty disclosures for this activity are as follows—
Dr. Gonzalez-Angulo receives grant/research support from Abraxis Oncology, Genomic Health, Inc, Novartis Oncology, and Roche Diagnostics, and is a speaker for Lilly Oncology.
Dr. McCune receives grant/research support from PDL Biopharma, has been an author for Educational Concepts and McGraw-Hill, and is on the scientific advisory board for Gateway for Cancer Research.
Dr. O’Regan is a speaker for Genentech and Genentech Health, and receives grant support from Abraxis BioScience, Inc, and sanofi-aventis U.S.
Presenting today is Dr. Ruth O'Regan, MD Director of Clinical and Translational Breast Cancer Research, Director of the Hematology/Oncology Fellowship Program, and Associate Professor of Hematology/Oncology in the Winship Cancer Institute at Emory University in Atlanta, Georgia.
A case study applying the data to a real-world scenario will be presented by Dr. Jeannine McCune, PharmD, Associate Professor at the University of Washington School of Pharmacy in Seattle, Washington.
Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Thank you again for joining us. Dr. McCune will now introduce the case study.
Slide 3: Thank you. Now we will go to our patient presentation.
Slide 4: A 57-year-old postmenopausal woman presents with a self-identified lump on her left breast. Patient history is negative for cardiac disease. She then undergoes mammography and subsequent biopsy.
Slide 5: She is ultimately diagnosed with stage III breast cancer of infiltrating ductile carcinoma histology, T3N1M0. Patient undergoes mastectomy, which subsequently reveals a 5.5-cm tumor, 2 of 12 positive nodes. The systemic workup is negative for metastases. The tumor characteristics are nuclear grade 3, estrogen receptor or ER positive, progesterone receptor or PR positive and also HER-2/neu positive.
Slide 6: The questions for consideration in this patient case are, based on her presentation, what is the next step in the course of treatment? What pharmacologic therapy options are available for this patient based on her history and presentation and, if adverse effects occur, what alternative treatments should be considered? I will now turn things to Dr. O'Regan for her presentation.
Slide 7: Thank you, Dr. McCune. We will now focus on the main presentation.
Slide 8: So the first slide we are going to look at here is looking at some general statistics for breast cancer. As you know, breast cancer is the most frequently diagnosed cancer among women. In 2007, it was estimated that there would be 180,000 new cases in both men and women and that there would be 40,000 deaths from breast cancer in the same timeline. Overall, breast cancer accounts for about a quarter of all estimated cancer incidence among women, and, by age 50, the chance of a woman getting breast cancer is 1 in 50, but this increases to 1 in 8 over the lifetime risk, which is because older women are more likely to get breast cancer than younger women.
Slide 9: In terms of economic burden of breast cancer, according to a study that was done by Barron et al, looking at per-patient per-month medical costs, the mean adjusted per-patient per-month medical cost in patients with breast cancer is about $4400, with hospitalization making up the greatest portion of the cost. Cost for control patients is about $3300. That is a significant difference. The projected annual cost was almost $13,000 over the cost of treating the control patients—so, clearly, a marked economic burden of breast cancer.
Slide 10: Now, what we are going to focus this presentation on specifically is HER2-positive breast cancer. Overall, about 25% of breast cancers are considered HER2/neu positive because they overexpress the HER2/neu protein or have gene amplification of HER2/neu. And what this translates into is about 50,000 cases of breast cancer diagnosed annually are HER2/neu positive. HER2-positive cancers have been demonstrated to have an aggressive course with the high likelihood of early metastasis, and what has been shown in a number of studies is that survival is significantly worse for patients with HER2/neu-positive cancers, but this was before we had HER2-directed therapies that have changed the biology of these cancers. But, basically, HER2/neu-positive breast cancer is a significant cause of morbidity and mortality.
Slide 11: This is looking at survival curves for patients with stage I, II, and III breast cancer—a large set of 900 women who either had HER2/neu-negative cancers by the fluorescence in situ hybridization assay or HER2/neu-positive cancers. And what they found was that the survival was significantly worse for the patients with HER2/neu-positive cancers. And the other thing just to point out here is how rapidly the curve separates in favor of the patients with HER2/neu-negative cancers doing better. You can see that after the first year, the curve starts to separate. As you will see when we start talking about the trastuzumab studies, this is why we saw the benefit of trastuzumab so early in these studies.
Slide 12: This is just looking at this a slightly different way. This is gene expression data which is basically focusing on particularly HER2/neu-positive, hormone receptor-negative cancers. This is work that was done in which breast cancers had gene expression analysis done, and the breast cancers were divided into about 4 or 5 different subtypes, each of which have their own biology in terms of rate of distant metastasis and overall survival. If you can just focus on the HER2-positive cancers, what you see is that they have a very high recurrence rate, especially early on, within the first 2 years, and you can see their survival is really very poor. But again this was before the widespread use of trastuzumab to prevent recurrence in these patients.
Slide 13: Now we are going to look at the definition of HER2 positivity.
Slide 14: Just in terms of background, the HER2 receptor is a member of a family of transmembrane receptors called the epidermal growth factor receptor family. You can see in this diagram, there are 4 receptors named HER1 through HER4. The natural ligand for all of the receptors is known except for HER2. We still do not know what the natural ligand for HER2 is. And you can see that 3 of the receptors have a tyrosine kinase domain, which basically sets off phosphorylation cascades within the cell leading to increased cell proliferation. One of the important things to know about these receptors is that in order to be activated, they either have to dimerase with their own receptor or to another receptor from the family. So, for example, HER1 can homodimerase to itself or it can heterodimerase to the HER2 receptor, and this is required for activation of phosphorylation cascades. The reason to mention this is that it is possible that an agent that targeted more than one receptor could have some advantages over an agent that perhaps just targeted a single receptor.
Slide 15: Now, the definitions of HER2 positivity are twofold. The first one is overexpression, which basically is defined as an abnormal increase in the number of HER2 protein receptors on the cell surface. So if you look at the cartoon, you have got your normal breast epithelium that has about 20,000 receptor molecules. The HER2-positive one you can see there is up to 2 million receptor molecules. The other definition is amplification, which is an abnormal increase in the number of HER2 gene copies in the cell nucleus. Again, you can see the normal cell and the amplified cell. Now there is pretty good correlation between HER2 overexpression and HER2 amplification. Although it is not complete concordance, there is very good concordance.
The way that these 2 tests are performed, overexpression of the HER2 protein is detected by immunohistochemistry antibody test, which I will show you in the next slide, and the amplification is detected by a fluorescence in situ hybridization test.
Slide 16: This shows the example of immunohistochemistry staining for HER2/neu. It is a membranous receptor, so you would expect to find the staining on the membrane of the cell. If you look at the IHC 3+, which is on the right-hand part of the slide, you can see clearly the staining for HER2/neu around the membrane. Conversely, if you look at the IHC 0 side, you see really no staining at all for HER2/neu. The IHC 1+ has very minimal staining, and very few of these are actually really considered HER2 positive. However, the IHC 2+, up to a quarter of these are actually HER2 positive by gene amplification and would potentially benefit from HER2-directed therapies. So if you see an IHC 2+ tumor, you always check the fluorescence test to see if there is gene amplification.
Slide 17: This is just an example of fluorescence in situ hybridization or FISH test. The way this is performed is they have 1 probe that targets chromosome 17, which is the chromosome that HER2/neu is on, and another probe that targets the HER2 gene. In the normal cell, there should be equal copies of both the HER2 gene and the chromosome 17 gene. In the HER2-amplified cell, obviously, there will be more copies of the HER2 gene compared to chromosome 17. So, if you look at the normal cell, there are equal copies of HER2 and chromosome 17 compared to tumor cells, where there is significantly more expression of the HER2 gene compared to the chromosome 17 gene.
In terms of false positive, the results are always given as the ratio of the HER2/neu gene to the chromosome 17. A ratio of greater than 2.2 is considered positive; a ratio of less than 1.8 is considered negative. And there is an equivocal group, which is between 1.8 and 2.2, which, again, these patients are problematic because you are not certain whether they should get trastuzumab or not. There are some labs that use number of HER2 gene copies instead of the ratio that I have shown here.
Slide 18: Moving on to treatment of HER2-positive breast cancer, just an overview of how we treat early-stage breast cancer.
Slide 19: There are really 2 components, a local therapy that is directed at the breast itself, which is made up of surgery plus or minus radiation therapy and then, systemic therapy, the role of which is to eradicate micrometastatic disease from the cancer. This, as we will see in a few minutes, is based on the expression of certain proteins in breast cancers and can range from hormonal therapy to chemotherapy, biologic therapy, or combinations of all 3 of these.
Slide 20: Just a little bit more about local therapy. For breast surgery there are 2 options, either mastectomy, where you remove the whole breast, or breast-conserving surgery, where you remove the tumor and the surrounding tissues. The lymph nodes are always assessed, and most recently, we do what is referred to as sentinel lymph node biopsy, where you inject a dye around the tumor bed or into the nipple, this will drain to the lymph node that is draining the breast. If you remove this lymph node and it is negative, what it means is that there is a less than 5% chance that there will be positive lymph nodes in the axilla. If however the sentinel lymph node is positive, you would have to go and do a full auxiliary lymph node inspection. The obvious advantage of sentinel lymph node biopsy is that you take out less lymph nodes and, therefore, there is the decreased likelihood of increased morbidity, particularly with lymphoedema. Radiation therapy is given to all patients who have breast-conserving surgery and also certain patients who have a mastectomy, particularly if they have multiple involved lymph nodes.
Slide 21: In terms of systemic therapy, the decisions are made based on a number of factors, including nodal involvement, the size of the tumor, the grade of the tumor, but most importantly, we select our therapy based on the expression of HER2/neu and also the hormone receptors, estrogen receptor, and progesterone receptor. Chemotherapy is indicated for the majority of patients for most tumors greater than a centimeter in size and certainly for any tumor that has lymph node involvement. The exception with the node-negative cancer is the estrogen receptor-positive cancers because we now have a gene expression analysis that is able to quantify the benefit of chemotherapy in ER-positive, node-negative breast cancer. Chemotherapy is certainly discussed with patients if their cancers are triple negative, which means they do not express ER, PR, or HER2/neu. If they are HER2 positive, chemotherapy is almost always given, and if the tumors are high grade.
Slide 22: Hormone therapy has been around for many years. It is only effective if the cancers are ER and/or PR positive. The selective estrogen receptor modulator tamoxifen decreases recurrence rates by about 50% in both pre- and postmenopausal women. In postmenopausal women, the aromatase inhibitors, such as anastrozole, exemestane, and letrozole, either alone or after 2 to 3 years of tamoxifen have been found to be more effective than 5 years of tamoxifen.
Slide 23: Now in terms of the treatment of HER2-positive breast cancer, the treatments are outlined on this slide. Chemotherapy is almost always given for these cancers. Trastuzumab, which as you see is an antibody that targets the HER2/neu, it is given in combination with chemotherapy. Lapatinib, we will discuss in a few minutes, is a tyrosine kinase inhibitor that is approved only at this time point for metastatic breast cancer when patients have progressive disease on trastuzumab. Potential future treatments include combinations of trastuzumab and lapatinib and the use of lapatinib in trastuzumab-naïve patients. Pertuzumab, which is an antibody that targets HER2 in a different place on the receptor to trastuzumab, and then other growth factor inhibitors and molecular targeting agents.
Slide 24: Now before we head to the widespread use of trastuzumab, there was a number of studies that evaluated chemotherapy in HER2-positive breast cancer. The good news is that multiple chemotherapy agents have activity in HER2-positive breast cancers. Anthracycline-based regimens have been found to be more effective than CMF, which is an old regimen. Additionally, the addition of paclitaxel after adriamycin-cytoxan in patients with node-positive breast cancer has been seen to be especially effective in HER2-positive cancers. The platinums, which are not that widely used in breast cancer, do appear to be effective in HER2-positive breast cancers.
Slide 25: Now we are going to talk a little bit about trastuzumab. Trastuzumab is a humanized anti-HER2 antibody, which is shown on this slide. It targets the HER2 protein with high affinity and specificity. What this slide is showing you is that it is 95% human and only 5% murine, and that basically means that the likelihood of having immunologic reactions or allergic reactions to this drug are actually quite low because it is mainly a humanized antibody. Now, when trastuzumab was initially developed, it showed some modest activity as a single agent in HER2-positive preclinical models. What they noted, however, was that there was marked synergy between trastuzumab and certain chemotherapy agents in HER2-positive breast cancers.
Slide 26: This is some preclinical data looking at HER2-positive breast cancer cell lines. This is looking at the synergy between trastuzumab and various chemotherapy agents. What this shows you is that combination index—if the combination index is less than 1, it is synergistic; if it is equal to 1, it is additive; if it is greater than 1, it is considered nonadditive. So you can clearly see here that the good news is that many of the chemotherapy agents that we use are synergistic with trastuzumab—you can see them listed there. To point out particularly 2 combinations that are particularly effective are the taxanes with the platinums. As you can see, there is synergy with a lot of other agents, as well. And almost all of these drugs have been examined in patients with metastatic HER2-positive breast cancer given concurrently with trastuzumab and have been shown to be effective. In the additive line are the anthracyclines and paclitaxel, and I will explain in a few slides that we do not give anthracyclines with trastuzumab because of the risk of cardiotoxicity. The nonadditive side, essentially, is methotrexate and 5-fluorouracil. In fact, with regards to 5-fluorouracil, an oral form of that drug, called capecitabine, has actually been shown in clinical studies to be at least additive with trastuzumab.
Slide 27: Now, the pivotal trial that led to the initial approval of trastuzumab in the metastatic setting is shown on this slide. This was a study of patients with metastatic breast cancer, HER2 positive, that had not had prior chemotherapy for metastatic breast cancer. They are essentially randomized to either chemotherapy alone or chemotherapy plus trastuzumab, but they were stratified based on whether they had had an anthracycline as adjuvant therapy or not. Then the patients that had not had prior adjuvant anthracycline who were randomized between AC alone or AC plus trastuzumab and the patients who had had prior adjuvant AC, they were randomized to paclitaxel alone or trastuzumab plus paclitaxel. You can see that there was an extension study, if the cancers progressed.
Slide 28: Now, looking at time to progression from this study, what they noted overall, looking at the patients overall and looking just at the patients who got paclitaxel was that there was a highly significant improvement in time to progression in the patients who got trastuzumab plus chemotherapy compared to chemotherapy alone. You can see the curve for overall, a significant P value. You can see also for the patients who got paclitaxel, again a significant P value.
Slide 29: This is looking at overall survival on this study and again, we are looking at all of the patients in the study here. The patients who got trastuzumab plus chemo versus the chemotherapy alone, there is a 5-month advantage in terms of survival for the patients who got trastuzumab plus chemo compared to chemotherapy alone. This is all the more notable because the patients in the chemotherapy-alone arm, many of them went on to get trastuzumab because it was available by compassionate care at the time of disease progression, and that is what is shown in the little table to the right of the slide. So although there was a crossover to trastuzumab from the control chemotherapy arm, the patients who got trastuzumab plus chemotherapy, as you can see, had a significantly improved survival.
Slide 30: What was the downside? Well, the surprising result of this study, but very important one, was the fact that in the patients who got anthracycline/cyclophosphamide plus trastuzumab, there was a marked increase in cardiomyopathy and CHF rates. This histogram is showing you the rate of cardiomyopathy in various groups on this study. You see there 27% cardiomyopathy for the patients who got AC plus trastuzumab versus 8% in the control group. This is the reason that we do not use trastuzumab with anthracyclines. But in the paclitaxel-treated patients, the rate was only 1% in the chemotherapy-alone group versus 13% in the paclitaxel plus trastuzumab group. The reason for this is if you remember all of the patients in the paclitaxel/trastuzumab group had previously gotten an anthracycline. So what we know about the cardiomyopathy associated with trastuzumab is that if you do not get an anthracycline, the patient is not at risk—does not appear to be at an excess risk—of getting a cardiomyopathy. So in some way, the anthracycline sensitizes the heart to the effects of trastuzumab; the molecular base of this is not understood.
Slide 31: Now we are going to look at 3 studies that have looked at the use of trastuzumab for patients with early-stage breast cancer. In other words, adjuvant studies. The first one is called the joint analysis. It actually combines 2 fairly large trials that were done in the United States, the NSABP B31 trial and the intergroup NCCTG 9831 study. The reason they were combined is because they had a very similar design. The control arm on both of these studies, patients got 4 cycles of AC followed by paclitaxel. The only difference was that in the NSABP study, paclitaxel was given every 3 weeks, versus in the intergroup study, it was given for 12 weeks. In this investigational arm on both of these studies was AC followed by paclitaxel with trastuzumab starting with the paclitaxel given weekly for a total of a year. So you can see that they got the trastuzumab throughout the paclitaxel and then, as a single agent for a total of a year.
Slide 32: Now, here are the updated results from this study. This is at a follow-up of 2 years, and what they noted was that although the follow-up was very short, there is already a significantly improved outcome for the patients who got the trastuzumab with chemotherapy compared to chemotherapy alone. If you look at the benefit at 3 years, it is about a 10% absolute benefit. That works out as a significant 50% overall improvement in disease-free survival for the patients who got chemotherapy plus trastuzumab.
Slide 33: This is the overall survival curves at 2 years. Again, this is statistically significant—about a 2% absolute benefit at 3 years with about one third of those events being reported. Again, this is statistically significant in favor of using trastuzumab with chemotherapy compared to chemotherapy alone.
Slide 34: The second study was the BCIRG study, which is shown here. In contrast to the joint analysis that I just showed you, this study allowed not just patients with node-positive breast cancers to enter, but also patients with high-risk, node-negative cancers. High-risk, node-negative was described really as any cancer over a centimeter if they are ER negative, but over 2 cm if they were ER positive. All of the patients on this study have to have a FISH-amplified cancer. In other words, they have to have the HER2 gene amplification. They were then randomized into these 3 arms. The first arm is very similar to the control arm of the joint analysis, 4 cycles of AC followed by 4 cycles of docetaxel, the other taxane. The first trastuzumab arm is 4 cycles of AC followed by 4 cycles of docetaxel with trastuzumab starting with the docetaxel given weekly throughout the chemotherapy and then, every 3 weeks after that for a total of a year. And then there is this non–anthracycline-containing arm, which was based on the preclinical synergy data I showed you earlier, where patients got docetaxel in combination with carboplatin. Because there was no anthracycline being used, these patients would start trastuzumab at the time of the chemotherapy—it was given weekly through the chemotherapy and then every 3 weeks after that for a total of a year.
Slide 35: Here are the results of this study; it is second interim analysis. What it basically shows is that the patients who got trastuzumab, regardless of whether they got it with an anthracycline or not, had a significantly improved disease-free survival compared to the control-treated patients. The absolute benefit is about 6% comparing AC/docetaxel/trastuzumab with the control group and 5% for the docetaxel/carboplatin/trastuzumab arm compared to the control.
Slide 36: This is looking at overall survival, and it really shows the same results. Overall survival was significantly improved in the patients who got trastuzumab regardless of what chemotherapy regimen was used compared to the control arm.
Slide 37: The last trial is referred to as the HERA trial, and this is slightly different from the trials I have just shown you in that trastuzumab is actually not given in combination with chemotherapy. But in this trial, women who had HER2-positive, early-stage breast cancer who had already received chemotherapy for at least 4 cycles were randomized to either an observation arm, a year of trastuzumab given every 3 weeks, or 2 years of trastuzumab given every 3 weeks. The 2-year arm of this study is not available for analysis at this time point, so what we are going to look at is a comparison of 1 year of single-agent trastuzumab with observation. Because of the positive results of this study at a year of follow-up, the patients on the observation arm were offered an option to switch to trastuzumab at that time point. So there is an analysis now of the intent-to-treat population and also a group that were sensitive at the time of switch which is going to look at the intent-to-treat population today.
Slide 38: This is disease-free survival and despite the fact that the trastuzumab was not given with chemotherapy, it was a highly significant improvement in disease-free survival for 1 year of trastuzumab compared to observation in this study. The absolute benefit was 6%, and you can see, it is highly statistically significant.
Slide 39: Likewise, when you look at overall survival, again, there is a significant overall survival advantage of about 3% for using trastuzumab compared to observation. Again, you can see it is statistically significant.
Slide 40: Just to summarize the efficacy of trastuzumab in the adjuvant setting, all of these 3 trials, in fact, 4 trials have shown that trastuzumab either alone or in combination with chemotherapy significantly improves both disease-free and overall survival in patients with HER2-positive breast cancer. As I alluded to earlier, the follow up of these trials is quite short, but the fact that we are already seeing positive results is a reflection of the aggressiveness of HER2-positive cancer.
Now, we are going to talk about some of the downsides. The main downside of trastuzumab is this risk to the heart and the risk of cardiomyopathy. This is a table basically quantifying the percentage of patients on each of the studies who developed symptomatic congestive heart failure on these studies. The NSABP study, you can see a 4% rate of cardiac events in the patients who got trastuzumab compared to 1% of the control group. This group of patients was very well studied, and the trial would have had to have been discontinued if the difference between the control and trastuzumab arms was 4% or greater. You can see that it was not, and that is why the trial reached accrual.
The intergroup study, there was no events in the control arm, but a 3% rate in the concurrent arm and 2% in the sequential arm, which I did not show you, in which patients got AC followed by paclitaxel followed by trastuzumab. Importantly, the BCIRG study, which I showed you, had an event rate of 1% in the control arm, that is the AC/docetaxel arm; a 2% rate in the AC/docetaxel/trastuzumab arm; and a 1.3% rate in the TCH, or docetaxel/carboplatin/trastuzumab arm. So, in other words, there is no significant difference between the non-anthracycline trastuzumab regimen and the control group, and for patients that we consider at high risk of developing cardiomyopathy from trastuzumab, this is certainly a reasonable regimen although it is not FDA approved as yet.
The HERA study, as you can see, had a low event rate of 1% on the trastuzumab arm versus the control arm. There is some data suggesting that there are patients that are at higher risk with trastuzumab for related cardiac problems, these include patients over the age of 50 or patients that have borderline ejection fractions before starting chemotherapy.
Slide 41: Now just a few minutes on lapatinib. We mentioned lapatinib earlier, and lapatinib is not an antibody, it is actually an oral tyrosine kinase inhibitor that targets the tyrosine kinase domain of both HER2 and HER1. So it may offer some advantages over trastuzumab because it not only targets HER2, but it also potentially blocks the effects of the heterodimerization of HER1 and HER2 that is known to occur.
Slide 42: The study that we have with lapatinib is in patients with metastatic breast cancers. These are patients with HER2-positive metastatic breast cancer who had previous treatment with an anthracycline, taxane, and trastuzumab. In fact, to enter this study, patients really had to have progressive disease on trastuzumab. The plan was to randomize over 500 patients to either capecitabine alone or to capecitabine plus lapatinib, a completely oral regimen.
Slide 43: In terms of the demographics of the study, I just want to point out 2 things here. First of all, almost all of the patients in the study had experienced disease progression while on trastuzumab. Secondly, the interval from the last dose of trastuzumab prior to going on this study was less than 4 weeks in about one third of the patients and less than 8 weeks in about two thirds of the patients. Now the reason this is important is because trastuzumab has a very long half-life, so some of these patients certainly have been circulating trastuzumab from the time they entered the study. As you can see, the number of patients is pretty much equal on both arms of the study, so it's very unlikely to have impacted the results.
Slide 44: The time to progression curve is shown on this slide, and what they found, again, very early on, was a marked separation of the curves in favor of lapatinib plus capecitabine versus capecitabine alone—overall, about a 9-week difference in favor of the combination arm. It is highly statistically significant as you can see.
Slide 45: In terms of side effects on this study, because this is a tyrosine kinase inhibitor, you would expect to see GI toxicity such as diarrhea and nausea, which was seen, also rash, which was also seen as well. But you can see, there were really very few grade 4 toxicities and really not a huge difference in grade 3 toxicities between the 2 arms of the study.
Slide 46: So in terms of the adverse effects of HER2-directed therapy, the main problem with trastuzumab is this risk of cardiomyopathy, which is relatively low, but can be serious. Other things that patients may complain of while they get the infusions are fevers and bone pain. With lapatinib, GI toxicity and rash are the most common things that are seen. Now one of the questions out there is, is lapatinib safer on the heart compared to trastuzumab? At this point, we do not know the answer to that question, because the only data we have is for the trial I just showed you, in which patients had already got trastuzumab who likely would have developed cardiac problems before entering this study, so it is not a clean population to look at in terms of the effects of lapatinib on the heart.
Slide 47: In terms of things that are coming down the pipeline, there are several adjuvant studies that are being developed.
Slide 48: The BETH study is looking at the addition of bevacizumab, which is an antibody that targets the VEGF ligand, which basically is an antiangiogenic approach in which you basically cut off the blood supply to cancer cells and also increase the penetration of chemotherapy into cancer cells. So this is basically patients that all get chemotherapy plus trastuzumab, and then they will be randomized between bevacizumab or not. This is eligible for a patient with node-positive and high-risk, node-negative HER2-positive breast cancers.
Slide 49: The other big adjunct study out there is called ALTO. This is a study again for HER2-positive, early-stage breast cancer in which patients will receive their chemotherapy, will then be randomized to either trastuzumab alone, lapatinib alone, trastuzumab followed by lapatinib or lapatinib concurrently with trastuzumab. The TEACH study was a phase 3 study that was basically looking to include patients with HER2-positive breast cancer who had not received adjuvant trastuzumab, so these would be patients that came to your clinic that basically had HER2-positive cancers before we started using adjuvant trastuzumab. They are eligible for the TEACH study, but obviously this is a limited amount of patients.
Slide 50: In terms of new novel agents coming down, pertuzumab, we talked about earlier, is another antibody that targets HER2, but at a different epitope to trastuzumab. For some reason, this agent appears to only have activity when given in combination with trastuzumab, and that is what is being looked at in metastatic studies. Insulin growth factor inhibitors, which are in development, have been shown to be able to reverse trastuzumab resistance in preclinical models. Additionally mTOR inhibitors appear to sensitize cells to the effects of trastuzumab.
Slide 51: So these are the guideline recommendations for HER2-positive breast cancer from the NCCN, which is very widely used to make treatment choices in all cancers. The recommendation is that adjuvant chemotherapy plus trastuzumab should be given to patients with node-positive, HER2-positive cancers and also node-negative, HER2-positive cancers that are greater than a centimeter. ASCO's recommendations are that all cancers should be tested for HER2/neu and treated appropriately.
Slide 52: So, in conclusion, I hope we have shown you that HER2-positive cancers are associated with an aggressive progression and a poor prognosis. However, the use of HER2-directed therapies, particularly trastuzumab in the adjuvant setting have been shown to markedly improve outcomes for these patients. Trastuzumab given in combination with chemotherapy improves survival both for patients with early-stage, HER2-positive cancers and also for patients with metastatic HER2-positive cancers. Lapatinib, an oral drug, is in clinical development but is approved at the moment for patients who have HER2-positive metastatic breast cancer in which the disease has resisted or progressed on trastuzumab.
Slide 53: Thank you. This concludes my presentation. We'll now turn it back to Dr. McCune for a discussion of the case study mentioned at the beginning of this activity.
Slide 54: We will now turn to our case resolution. Thank you very much for your time, Dr. O'Regan. To revisit this patient case, we have a patient who is diagnosed with hormone receptor positive and HER-2/neu-positive stage III breast cancer. Patient underwent mastectomy, and she must now undergo continuing therapy.
Slide 55: Her adjuvant therapy following mastectomy, systemic treatment, is administered via chemotherapy or hormonal therapy. This patient will receive chemotherapy with doxorubicin and cyclophosphamide or AC, and her hormonal therapy will be anastrozole as she is currently postmenopausal.
Slide 56: AC chemotherapy with doxorubicin cyclophosphamide will be initiated such that she will receive 4 cycles of the following doses—doxorubicin 60 mg/m2 IV every 3 weeks and then cyclophosphamide 600 mg/m2 IV every 3 weeks. During the 4 cycles of chemotherapy, the patient experienced intermittent nausea, gastrointestinal reflux, fluid retention, and fatigue.
Slide 57: Now we will discuss consideration of trastuzumab therapy. Based on the NSABP B-31 study, trastuzumab administration is feasible in the following patients. The first group is those patients without cardiac disease, specifically those that do not have congestive heart failure or other cardiomyopathy, a prior myocardial infarction, angina pectoris, cardiac arrhythmias requiring medication, severe conduction abnormalities, clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or poorly controlled hypertension.
Another group that can receive trastuzumab are those patients that do not have cardiac symptoms during AC and those patients who have an ejection fraction assessed with MUGA which is above the lower limit of normal and that ejection fraction which has not decreased by more than 15% from the ejection fraction assessed before starting AC. In this patient, they have no history of cardiac disease. The ejection fraction was 54% at the time of diagnosis and is currently, after receiving AC, 53%. And thus, this patient can be considered for trastuzumab therapy based on their cardiac status.
Slide 58: So, in this case, after completion of AC, the patient receives paclitaxel 80 mg/m2 IV weekly for a total of 12 weeks with concurrent trastuzumab, 4-mg/kg loading dose followed by 2 mg/kg weekly for a total of 51 weeks. Radiotherapy is then administered after completion of her paclitaxel, and then, following completion of her radiotherapy, this patient will receive anastrozole, 1 mg daily for 5 years.
Slide 59: Regarding this patient's cardiac function while she was receiving trastuzumab, her ejection fraction was stable at 53% after 6 months of trastuzumab administration. At her 9-month ejection fraction assessment, her ejection fraction fell to 30%—although the patient was asymptomatic with no shortness of breath, tachycardia, or other signs of cardiac dysfunction. However, based on the protocol NSABP B-31, trastuzumab needs to be held because of her cardiac dysfunction, although the patient still has approximately 15 weeks worth of trastuzumab therapy.
Slide 60: So, in conclusion, with this patient in the adjuvant setting, there is really no data that currently exists on the benefits versus the risk of 9 months versus 12 months of trastuzumab therapy. And if this patient does relapse, we should consider a first-line treatment for HER-2/neu-positive recurrence or metastatic breast cancer. Specifically, if her ejection fraction has improved, we could consider restarting trastuzumab or administering docetaxel or vinorelbine. Lapatinib and capecitabine administration is also an option in the event of relapse.
Slide 61: So to conclude again on this case, adjuvant therapy for early-stage breast cancer is increasingly being personalized based on tumor characteristics. Adjuvant chemotherapy and trastuzumab are currently the standard of care for HER-2/neu-positive breast cancer. And careful monitoring of cardiotoxicity is important for short- and long-term survival. This concludes my presentation. Thank you very much for your commitment to improving the care of breast cancer patients and your time spent participating in this continuing education program.
Next >>
