Vicente Valero, M.D.
Professor, Breast Medical Oncology
The University of Texas M. D. Anderson Cancer Center
Return to Current Topics in Oncology
Vicente Valero: Welcome to Current Topics in Breast Management and Oncology 2009. I'm going to cover the medical management of early breast cancer today. We have three major objectives. Initially, I will give you some general concepts, and then I will cover the predictive and prognostic biomarkers on treatment selection of patients with early breast cancer. I will discuss the clinical trials that support the role of adjuvant therapy in early breast cancer. I will cover biological therapy, chemotherapy, and well as hormonal therapy. Finally, I will briefly discuss some of the emerging therapy options that we are seeing in early breast cancer. Then I will give you my final remarks at the end of the presentation.
As you can see in this slide, breast cancer is very common in North America, Eastern Europe, Australia, and Argentina. And the other hand, it's very uncommon in the Far East, as well as in middle and central Africa. In the United States we estimate that 180,000 women developed breast cancer -invasive breast cancer-- in 2008. In addition, 40,000 women developed ductal carcinoma in situ. Therefore it's a very common disease. The good news is that we are seeing a decrease in the incidence of breast cancer. As you can see in this slide, as the decline for hormone replacement therapy prescriptions, we can see that there is a decrease in the estrogen receptor positive breast cancer that we can see it here on this slide. On the other hand, the estrogen positive breast cancer is unchanged.
What about breast cancer mortality? We have seen a decrease in breast cancer mortality in North America, as well as Occidental (Western) Europe, also seeing some of the decrease in mortality in Argentina and Uruguay. Why is that? Well, in part it's related to screening, and in part related to the use of adjuvant systemic chemotherapy in women with early breast cancer. So this is great news for our patients.
Once a patient has breast cancer, after loco-regional therapy, patients see the medical oncologist for systemic management of breast cancer. As you can see in the slide we look at different factors to select the optimal treatment for our patient. We look at co-morbidities, the adverse effects of our agents, as well as the therapeutic index. We look at patient factors as well as tumor characteristics, and ultimately we make a decision in collaboration with the patient.
A very common tool that we have used in the last ten years is "adjuvantonline". This is a free program that is on the Internet. It has incorporated different factors: patient characteristics, tumor characteristics, and the benefits of any adjuvant therapy that they have from randomized studies.
What are these characteristics? As you can see in the slide, we take for instance the tumor size, the age, we look at the number of lymph nodes, tumor grade, and we also incorporate the results of the Oxford Overview, about the relative reduction in risk which leads to the absolute benefit of therapies using first generation, second generation, third generation chemotherapy regimens, as well as first generation and second generation hormonal therapy.
Here is an example from "adjuvantonline". As you can see, this is a patient that is 62, is in perfect health, and has a Stage 1 breast cancer. The tumor is low grade, and estrogen receptor positive. The risk of relapse for this patient is estimated to be approximately 10 to 15%. In this case, the computer model gave us 15% risks at ten years. And as you can see in the slide, in red, this is the risk of relapse. This could be reduced by using hormonal therapy basically by half. 50% reduction, which leads to an absolute number of 7%.
On the other hand, with the addition of anthracycline based adjuvant therapy for six cycles to this patient will have a very marginal benefit with a very low therapeutic index. Therefore adjuvant chemotherapy is not considered in this group of patients.
On the other hand, if we have a patient with different characteristics--for instance, this slide shows a 35-year-old woman with a tumor that is grade 3, the tumor measuring 2.5 centimeters, and the patient has 6 positive nodes. The risk of relapse, as we can see, is substantial in this patient. This is the red bar, and the risk is approximately 75%. The introduction of chemotherapy will produce an absolute value of 28% by adding the same chemotherapy I mentioned earlier, an anthracycline- based therapy, for six cycles. So this is something that we do in every patient when we make a decision about chemotherapy and hormonal therapy in patients with HER-2/neu normal breast cancer.
This program has some weakness and some strengths. As you can see in the slide, lymphovascular invasion and HER-2/neu amplification or over-expression are not taken very well into the model, as well as those patients with small tumors, less than 1 centimeter. The benefit of trastuzumab based chemotherapy therapy has not been incorporated in the model yet, but still we believe this is a very important tool. No cost, and is very helpful to patients and clinicians, as well as physicians in training.
So what about new technologies? Well, as we have seen the evolvement and the discovery of the human genome, we started to look at the tumor genome. And so there are different groups that have been working on developing genomic signatures of patients with breast cancer as well as other neoplasias. Why is that? Well, sometimes one marker may have some weakness and if we have a multigene platform may it may strengthen our assessment about tumor risks as well as potential benefit with our therapies. And therefore we believe that the multi-gene expression data may allow us to discover new targets and to discover new set of genes that would determine which patients would be a higher or lower risk, and to try to deliver on the promise of delivering personalized medicine in this century.
So I'm going to show you a couple examples of this multigene platform, but you can see in the slides the evolvement, the evolution of the concept of breast cancer from the morphology to incorporation of single markers to the use of multigene platforms. And now we have four different types of breast cancers that we classify in 2009. As you can see, this include ER positive Luminal A, ER positive Luminal B, triple receptor negative, and HER-2/neu expression or over amplified, or as it's called HER-2/neu positive.
So here is one of the multigene platforms called "Mammaprint", a 70-gene predictive platform. This was developed in the Netherlands and as you can see here, these are the patients that relapse. They have certain genes in red, as well as genes in green, versus the ones who don't relapse. So we separate them by using this 70 gene platform. And the initial study included 78 patients, but later almost 300 patients were presented in a publication in the New England Journal of Medicine, and this includes 150 patients with negative node Stage 1 or 2 breast cancer. The majority of these patients did not receive any systemic therapy. So this is a prognostic signature.
And here you can see in the top of this slide the good prognosis and the bad -- poor prognosis signatures. If we focus on the node negative breast cancer, for instance, the ten year disease-free survival was 86% versus 44% for distant metastases in patients who have poor signature even though the patient has node negative Stage 1 or Stage 2 breast cancer. So this is a very important signature, and there is a European validation of this signature ongoing.
There is another signature that's called "Oncotype DX". This was developed by Genomic Health, and this includes 21 genes--16 genes that are (cancer genes) and 5 that are called reference genes. This platform is very useful in determining the benefit of adjuvant hormonal therapy and systemic chemotherapy in a group of patients with estrogen receptor positive, Her-2/neu normal, and node-negative breast cancer.
A couple of studies have been presented with this signature. The original one was to look at this platform to see if they can separate which patients were relapsed and which did not relapse after the administration of 5 years of tamoxifen, and the platform was able to separate those patients. In addition, this platform could be predictive for response to hormonal therapy and chemotherapy. For instance, in this slide you can see the NSABP- B 14 (study). We have patients who, after surgery, were randomized to placebo --at that time the standard of care-- versus the experimental arm, which was tamoxifen. And as you can see in this slide, in those patients that had what we call a low recurrence score, this shows that the addition of tamoxifen (in yellow) was preferable to placebo. On the other hand, those patients with a high recurrence score did not seem to benefit by the addition of tamoxifen to surgery in patients with estrogen receptor positive, node negative breast cancer. But as you notice, more than 35% of these patients have relapsed at 12 years, despite the patient having Stage 1 or Stage 2 breast cancer, node negative, ER positive breast cancer, and being treated with tamoxifen.
So does chemotherapy change the outcome of this group? Does chemotherapy increase (improve) the outcome of patients that have only been treated with tamoxifen? Well, there has been another study, called NSABP-B20. This study randomized patients to tamoxifen-- at this point a standard of care for ER positive, Stage 1, Her-2/neu normal breast cancer-- versus adding chemotherapy to this group of patients. So this is a randomized study. And in this study, as you can see, in those patients with a low recurrence score, the addition of CMF, or methotrexate/5FU-based therapy didn't seem to improve on the great outcome that these patients had after ten years-as you can see more than 90% of the patients were free of distant metastases at ten years. On the other hand, those at high risk-- with a high recurrence score-- tamoxifen (here in yellow), and chemotherapy followed by tamoxifen (in blue)--you can see there is a substantial decrease in the hazard ratio for relapse in those patients in yellow. On the other hand, adding CMF-based therapy substantially improved the outcome of these patients with an absolute difference of greater than 25% in those patients with a high recurrence score, using this particular technology.
So let me move on from selection to therapy, to the data that we have in adjuvant endocrine therapy, chemotherapy, and we'll touch bases at the end on biological therapy, and the introduction of bisphosphonate therapy.
Adjuvant hormonal therapy has been the first one to have a major impact in early breast cancer. The majority of the patients with early breast cancer have an estrogen receptor positive, hormone sensitive breast cancer, and this is the number of therapies that are available for adjuvant therapy for breast cancer: the ones that are commonly used today are tamoxifen, LH-RH agonists, and more recently aromatase inhibitors were introduced in the adjuvant therapy of breast cancer.
Let's go over the data with tamoxifen. Tamoxifen decreases the hazard ratio for relapse by approximately 50%. And that effect is long-lasting. At least we have information at 15 years. This has been a major therapeutic tool that we have for early breast cancer. And if you look graphically here, you can see in patients with ER positive early breast cancer, and we look at recurrence, and we look at 5 years of adjuvant therapy with tamoxifen, at 15 years we can see those patients in the placebo arm, 45% of the patients suffered a relapse versus 33% on the patient that received tamoxifen, with an absolute benefit of 12% that is long-lasting. It also impacts overall survival, as you can see on the other side of this slide.
So can we do any better than tamoxifen, a drug that we have had since 1973? Well the introduction of aromatase inhibitors has substantially increased (improved) the outcome of patients with advanced breast cancer, ER positive breast cancer, as well as early breast cancer. So the mechanism of action is that it blocks aromatase, which is the enzyme that converts androgens to estrogens, as you can see in this slide. By decreasing the estrogen levels, the microenvironment for estrogen receptor positive early breast cancer changed. That leads to improvement in the disease-free survival in multiple trials that have compared tamoxifen alone, versus tamoxifen followed by an aromatase inhibitor, versus tamoxifen, versus an aromatase inhibitor.
So here is the meta analysis of this initial trial. This compares aromatase inhibitors versus tamoxifen and there are two big trials that you can see that compare 10,000 – in this trial there were 10,000 patients, the combination of these trials. And then we have another 10,000 patients with the one that received tamoxifen followed by an aromatase inhibitor versus tamoxifen. So, a very large database.
So we take the first cohort: aromatase inhibitors (either letrozole or anastrazole) versus tamoxifen. We can see here in blue (versus orange), basically a 4% decrease in events (either contralateral breast cancer, ipsilateral breast cancer, local recurrence, or distant relapse) by adding an aromatase inhibitor. So an absolute percent of-4% in this setting. What about when we use sequential therapy? Again, we look at these 10,000 patients, we look at the gain at six years, and we can see the difference is 3.5% in favor of using the sequential approach of tamoxifen for two to three years, followed by an aromatase inhibitor for two to three years. So therefore these agents are recommended in the treatment ER positive early breast cancer, either as an up-front therapy or as a sequential therapy after tamoxifen.
So there are still some questions about endocrine adjuvant therapy. You can see them in the slide. And the main questions are: What is the role of ovarian ablation in combination with tamoxifen over tamoxifen? What is the role of aromatase inhibitors in pre-menopausal breast cancer after patients are rendered post-menopausal by the use of LH-RH agonists? And can aromatase inhibitors and tamoxifen used sequentially with LHRH agonists be superior to using chemotherapy in this setting? So there are some outstanding questions that have been addressed in several clinical trials.
What about in those patients with post-menopausal breast cancer? Which are the best aromatase inhibitors? What is the duration of aromatase inhibitors? What is the role of chemotherapy in early breast cancer-- estrogen receptor positive, node negative HER-2/neu normal breast cancer? What is the absolute benefit of chemotherapy in this setting?
So let's move on to chemotherapy. Chemotherapy has been around for many years. Initially, the cyclophosphamide based therapy such as CMF was used for many years. Anthracyclines were introduced in the late '70s and early '80s, and more recently in the '90s, Taxanes were introduced in the adjuvant therapy of high-risk early breast cancer. So if we look at the meta-analysis of all of these clinical trials, and we look at what we call the combination trials: for CMF therapy versus no chemotherapy, there was a 40% reduction in the rates of relapse by adding CMF therapy.
What about CMF therapy versus anthracycline-based therapy? Well, anthracyclines further reduced the risk in selected ER positive or ER negative, Her-2/neu normal or HER-2/neu amplified breast cancer in a select group of patients that will further reduce the risk by 11% with an absolute difference of approximately 3 or 4%, in disease-free and overall survival over CMF.
So what about the taxanes? Well, docetaxel and paclitaxel are proven in adjuvant (therapy of) early breast cancer at high-risk. And there have been many trials that document that the addition of taxane modestly, but statistically significantly reduce the risk of relapsing and also improves the chance of surviving by adding a taxane to an anthracycline- based regimen. Therefore, it is the current standard to provide patients with third generation taxane-based therapy, such as docetaxel, doxorubicin, cyclophosphamide (called TAC), or dose-dense AC followed by dose dense paclitaxel, and finally weekly paclitaxel times 12 followed by AC or FAC or FEC times four cycles are the most common third-generation regimens used in the U.S. and abroad.
I'm going show you a few trials that have addressed adjuvant chemotherapy in breast cancer. And you are seeing the questions here in this slide. I will cover: Which taxane? Is shorter (duration) as good as full adjuvant therapy? Is combination better than sequential? Are single agent oral therapies a substitute in the elderly to more toxic and longer regimens such as CMF or AC? What is the role of new agents different than taxanes and anthracyclines? And can we use a non-anthracycline regimen in the selected patient population with early breast cancer? So I'll cover these six questions very quickly.
This is the largest study that addressed the questions of which taxane and which schedule. It's called ECOG 1199. It was published in the New England Journal of Medicine last year. In this study, after four cycles of AC, patients received either weekly paclitaxel or weekly docetaxel, or every three weeks docetaxel, or every three weeks paclitaxel. Basically, the bar or the standard was at that point paclitaxel 175mg. every three weeks times four. In the experimental arm are paclitaxel weekly, docetaxel every three weeks, and docetaxel weekly. So as we can see in the primary analysis, there was no difference between paclitaxel and docetaxel, or (between) weekly versus every three weeks. However, in the secondary comparison we can see that weekly paclitaxel and every three weeks docetaxel seem to be slightly superior, but statistically positive over paclitaxel every three weeks. So my current recommendation is to consider either weekly paclitaxel or every three weeks docetaxel, if we're going to use a sequential regimen such as AC followed by a taxane. Again – docetaxel/ doxorubicin/ cyclophosphamide times six is another established FDA approved regimen in this setting.
What about -- can we get by with only using four cycles of therapy rather than six cycles of therapy or eight cycles of therapy? Well, here is the first study -- NSABP-B30 -- presented by Dr. Swain last year in San Antonio at the breast meeting. Here is the standard -- you can see AC times 4 followed by docetaxel times 4. Can we get by, by using a shorter regimen such as AT times 4, or TAC times 4? And the answer is no. Shorter regimens with patients with node positive, ER positive, or ER negative breast cancer was inferior to the standard regimen of six months, four cycles of AC followed by four cycles of docetaxel as you can see in the slide. This is the standard, these are the two experimental arms. These were inferior, and therefore there are no substitute regimens for the one in yellow, AC times 4 followed by T times 4.
Well, what about TAC versus combination regimen versus a sequential regimen? These regimens are FDA approved. This is AC times 4, docetaxel times 4, a common regimen, as you know paclitaxel times 4 was approved as the initial taxane based regimen approved by the FDA and other regulatory offices around the world. So, is any of the two better? And the answer is no. As you can see there is identical benefit with almost 80% of the patients free of metastasis and other breast cancer events at five years by either using TAC which would be 18 weeks (every three weeks times six cycles) versus AC followed by docetaxel (24 weeks). So there was no difference. So, either of these regimens would be an appropriate adjuvant therapy for patients with high risk, ER positive or ER negative, HER-2/neu normal breast cancer.
Well, what about -- can we get by with oral capecitabine as a regimen for the elderly? And elderly is defined in this particular study as 65 and older. Is that an appropriate definition? Well, let's take age to make it simpler. For women older than 65 the standard arm was CMF for six cycles or AC for four cycles. This study compared to capecitabine single agent therapy, every three weeks for four cycles. And this study was discontinued because it showed inferiority (in results). After having 600 patients in the study, this has been already published in the New England Journal of Medicine. As you can see, at the stopping the study, almost 90% of the patients on CMF and AC were free of disease, versus 80% (on the capecitabine arm)--a minus 9% absolute difference. So therefore, capecitabine as a single agent is not an appropriate regimen in this patient population.
What about new agents, new chemotherapy agents? Well this is a study from the United Kingdom where patients were randomized to receive the standard arm in the top--epirubicin/cyclophosphamide for four cycles, followed by paclitaxel for four cycles, versus epirubicin/cyclophosphamide for four cycles, and gemcitabine was added to paclitaxel. That combination regimen here, versus single agent here paclitaxel after receiving AC. Well, as you can see in the slide there was absolutely no difference. The hazard ratio was 1.0. Therefore, adding gemcitabine in this setting did not significantly increase the disease-free survival in this group of patients.
Can we get by, by using a non-anthracycline regimen in selected patients with HER-2/neu normal ER positive or ER negative breast cancer? This is a clinical trial launched by U.S. Oncology a few years ago and published and updated in the Journal of Clinical Oncology just last year. So this is a study with doxorubicin/cyclophosphamide for four cycles, which was one of the acceptable regimens in patients with node-negative HER-2/neu normal breast cancer, or even patients with 1 to 3 positive nodes, versus the experimental arm with a non-anthracycline regimen with docetaxel/cyclophosphamide. This regimen had an acceptable safety profile, and preclinically had shown some synergistic effect. It has shown some activity in the metastatic setting, so therefore this study was launched in 1997, a decade ago.
As you can see in the latest update early this year, you can see that AC (in blue here), was inferior to docetaxel/cyclophosphamide. The absolute difference was 6% in disease-free survival, and also was a 5% absolute difference in overall survival. So therefore, the use of docetaxel/cyclophosphamide in this setting is superior to doxorubicin/cyclophosphamide.
Is that better than the third generation taxane and anthracycline based regimens that I just briefly mentioned to you in the previous slide? Nobody knows. There is a clinical trial right now, TAC times six cycles versus TC (docetaxel/cyclophosphamide) for six cycles, with or without bevacizumab, that's trying to address this particular question: can we get by without using an anthracycline- based regimen in patients with ER positive or ER negative HER-2/neu normal breast cancer? This is a very important question in clinical research and early breast cancer.
What about the role of neoadjuvant chemotherapy or primary systemic therapy versus adjuvant therapy? Well, there has been a recent meta-analysis that shows these results. Why primary systemic therapy? Well primary systemic therapy or neoadjuvant chemotherapy, or induction chemotherapy will provide us with in-vivo response to our therapies. So it makes sense. Also we're provided with an early surrogate marker of pathological complete remission or outcome, rather than waiting for 10 years follow up. It also, in some patients, would enhance the possibility of breast conservation, or in some patients with locally advanced breast cancer, it will allow them to become operable. Therefore this is the potential advantage of primary systemic therapy.
Is that superior or inferior to adjuvant therapy? And the answer, as you can see in mortality or in the disease progression, there was absolutely no difference in nine randomized studies that included almost 4,000 patients. So either adjuvant or neoadjuvant systemic therapy is considered to be an acceptable systemic therapy for patients with early breast cancer.
Moving to biological therapy, we have seen emerging the role of biological therapy in breast cancer in the last five years. Several important randomized studies in the adjuvant setting and two small neoadjuvant studies introducing trastuzumab for biological therapy of patients that have HER-2/neu amplified breast cancer have been recently presented or published.
So here is the cartoon (illustration) demonstrating that this transmembrane protein that's called HER2 (Human epidermal receptor2). And we can see that we target this either by affecting the extracellular domain of the protein, or the intracellular domain of the protein, we may change the natural history of HER-2/neu amplified breast cancer. And that has been proven in the metastatic setting.
So therefore several major randomized studies were launched in the late '90s to introduce trastuzumab. Here is one of the most important studies, and it's called NSABP-B31. This included patients with node positive breast cancer. They had to have over-expression of HER2 protein or amplification of the HER2 gene, and half of the patients in this particular study received AC times four followed by paclitaxel either every three weeks times four, or weekly times 12, with or without trastuzumab. Then the intergroup study N9831 launched a similar study with a difference that there was a third arm in the middle that rather than giving trastuzumab with paclitaxel, it was given sequentially.
The data I'm going show you is for arms 1 and 3 and it was combined with a previous study. Leading to include 4,000 patients in the study, this is the latest update after the seminal publication by Dr. Romond in the New England Journal of Medicine, this was presented in our meeting in 2007. And we can see that (in blue), the introduction of trastuzumab to a chemotherapy based regimen showed a substantial improvement with an absolute difference almost reaching 10%, over AC and paclitaxel alone without trastuzumab. So therefore this combination is now currently available to our patients with early breast cancer, either with node negative, node positive HER-2/neu amplified over expressed breast cancer.
There's been another seminal study, BCIRG 006. The difference with the previous study is that this include non-anthracycline regimen. The control arm was AC times 4, followed by docetaxel times 4, with or without trastuzumab, and then we have a third arm that has carboplatin, docetaxel and trastuzumab.
As you can see in the slide (in red, as well as in blue), the arms that contain a trastuzumab-based therapy were statistically better than the ones with chemotherapy alone. This is in the whole patient population. And also in 1,000 patients with node-negative breast cancer with an absolute difference greater than 5% with the introduction of trastuzumab to chemotherapy versus chemotherapy alone in node-negative breast cancer.
Well, what was the price of this therapy? Well, there is an increase in cardiotoxicity that ranged from 0.5 to 3%, with the introduction of trastuzumab to chemotherapy, versus chemotherapy alone. So patients receiving trastuzumab-based therapy in the adjuvant setting need to be monitored carefully for cardiac toxicity.
So there are some unanswered questions in this setting. What is the optimal duration of trastuzumab therapy? What is the best sequencing? Do we have other target therapies that are superior to trastuzumab? And there are different clinical trials introducing bevacizumab as well as lapatinib in this setting.
What about bisphosphonates? You have seen that recently, the introduction of bisphosphonates in the adjuvant setting has been very important. There are major clinical trials addressing this issue. One of them was just recently published in the New England Journal of Medicine, and it was 1,800 patients that received either LH-RH agonist Goserelin with tamoxifen, or with anastrozole, plus or minus zoledronic acid. As you can see (in red) in this study, it shows an improvement in disease-free survival in patients that receive hormonal therapy plus zoledronic acid versus hormonal therapy alone.
So I showed you some data that adjuvant systemic therapy substantially decreases the risk of relapse including improved survival with endocrine therapy, with chemotherapy, with anti HER2 therapy and now we start to see that with zoledronic acid. Mortality benefits are also seen, obviously more modest because of the competing causes of death.
So where are we going? One, we're trying to develop new clinical trials that will include new targets. And there are studies ongoing, for instance, with bevacizumab, and in advanced disease we started to use the introduction of the PARP inhibitors as well as the mTor inhibitors. So some of these are in early development, some of them in metastatic setting, some of them bridging the adjuvant setting such as lapatinib and bevacizumab, as well as the biophosphonates.
So to conclude we have seen significant progress that has been the integration of new therapies such as breast conservation, sentinel node, new hormonal therapies, new chemotherapy agents, and now biological therapies to the treatment, multi-disciplinary treatment of breast cancer. We have identified some predictors and prognostic markers, and some of them are in evolution, but some already play a role in the clinic. It seems that we started to see the light to start producing enough information to individualize patient therapy. I think there are many targets out there that because of the limitation of time we unable to cover. But I think that it is going to be crucial to start to be able to select patients to our therapy more appropriately, also to select patients to different therapies, and also look for different toxicities. So the future looks bright and promising at this point. I would like to thank you for your attention, thank you for joining us today.
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