The absolute benefit from chemotherapy for both older and younger patients appeared most significant in ER-negative populations.

Transcription

1 Hello, my name is Diane Hecht, and I am a Clinical Pharmacy Specialist at the University of Texas MD Anderson Cancer Center. It s my pleasure to talk to you today about the role of chemotherapy in this Breast Cancer Survivorship series. The objectives of today s presentation is for you to be able to describe the current prognostic and predictive factors with clinical utility for breast cancer; to interpret the rationale for systemic treatment of early stage breast cancer; to recognize patients with operable disease who are likely to benefit from systemic treatment with chemotherapy and/or biotherapy in addition to local therapy; to identify chemotherapy and biotherapy regimens which have demonstrated benefit in the treatment of early breast cancer and are considered standard of care; and lastly, to identify the current treatment approach with systemic chemotherapy and biotherapy in patients with operable disease. I d like to first start with a --- a quick review about breast cancer and just to remind everyone that this is not one homogenous disease. It s actually a very heterogenous disease and it s driven by multiple genetic alterations and molecular events resulting in identification of unique subsets of patients and tailored treatment based on risk versus benefit principles. Because breast cancer is a heterogenous disease, treatment with local and/or systemic therapies is based on prognostic and predictive factors. Prognostic factors are those factors that in the absence of systemic therapy correlate with the natural history of the disease, reflect the inherent aggressiveness of the cancer, and are associated with the likelihood of distant recurrence. Predictive factors include biomarkers that provide information that predicts response to therapy. Prognostic factors in clinical practice include the following listed on this slide: the number of axillary lymph nodes, the tumor size and grade, the patient s age are all very important factors, including a patient s comorbidities. These happen to be the strongest predictive factors forecasting future recurrence or death from breast cancer. Predictive factors utilized in clinical practice today include the hormone receptors status as well as the Human Epidermal Growth Factor Receptor 2, or HER2/neu, amplification or overexpression. The estrogen or --- and/or progesterone receptor predict response to hormonal therapy whereas the HER2/neu amplification predicts response to trastuzumab therapy which is a monoclonal antibody directed against the HER2 protein. It s also possibly predictive of response to anthracyclines as we ve seen this demonstrated in retrospective analyses. The use of prognostic and predictive factors al --- allows us to limit the use of toxic drugs to the patients most likely to benefit. There s no reason to give these toxic drugs to patients that aren t likely to benefit from them so we want to be

2 very careful and very thoughtful about those patients that we administer chemotherapy to. Computer modeling is now available and has greatly changed our ability to better predict patients who should receive chemotherapy. This computer-based modeling or algorithm combines tumor and patient-related factors to de --- to predict --- [excuse me] --- clinical outcome and it really helps us address the risks versus the benefits of additional systemic therapy after local therapy has completed. Lastly is genetic profiling. These gene expression-based prognosticators have been extremely important as well. We --- Using DNA microarray technologies to provide this gene expression profiling and they have identified five major subtypes of breast cancer using these gene expression profiles. They are luminal A and B, the basal like, HER2 enriched, and then lastly, normal breast tissue like. In retrospective analyses these gene expression subtypes are associated with differing relapse free and overall survival. So what s the rationale for systemic therapy if a patient s already had local therapy? The rationale is this: Even though we don t see clinical evidence of disease either clinically or pathologically, radiologically, there s a good chance that there are micrometastases in the body that we need to eradicate. So systemic therapy provides us an opportunity to eliminate these micrometastases. And as it --- it states on the slide, clinically detectable cancer has had an opportunity to establish distant micrometastases and that s approximately 30 doublings. So it s very important, again, that we address these micrometastases. The reduction of risk requires systemic treatment with either and/or chemotherapy, endocrine therapy, and possibly biologic therapy, again, along with the local treatment. Early stage breast cancer Stage I and II or locally advanced breast cancer which is Stage III has benefitted from systemic treatment. Again, this is where there is no evidence of metastatic disease but there s a high likelihood of recurrence. The goal here is curative. We want to reduce the likelihood of both local and distant recurrence. We can do that ei --- either --- [excuse me] --- one of two ways. We can administer adjuvant therapy or neoadjuvant therapy. Adjuvant therapy is when we give chemotherapy or biologic therapy after local therapy whereas neoadjuvant is as its sounds, administered preceding the local therapy. There have been randomized Phase III trials that demonstrated that preoperative therapy is equivalent to postoperative therapy in both disease free and overall survival. Neoadjuvant therapy as I stated earlier can be given in the form of chemotherapy, biotherapy, and less frequently, hormonal therapy. The National Surgical Adjuvant Breast and Bowel Project, a cooperative group, demonstrated

3 the equivalency of preoperative chemotherapy to postoperative chemotherapy in two large trials: the B-18 and the B-27 protocols. The B-18 was approximately 1,500 patients and the B-27 was approximately 2,400 patients. Both of these studies demonstrated the equivalence of preoperative therapy with postoperative therapy. It also demonstrated that achievement of pathologic complete response in the breast tissue as well as the axillary node tissue clearly predicted a favorable long-term outcome in terms of disease free and overall survival. Now was --- what are some additional benefits in --- of neoadjuvant therapy? Well, for instance it may increase the rate of breast conserving treatment. You may have a very large tumor that can be reduced in size greatly with that chemotherapy or biotherapy, giving a much better cosmetic effect after surgery than had that chemotherapy or biotherapy not been given. It also renders inoperable tumors resectable. So there may be instances where tumors are so large that surgeons aren t able to operate and, again, the systemic therapy shrinks it down to a size where the surgeons can then operate on it providing a curative surgery. The last benefit is that we can take that tissue and we can look at it in the lab after the surgery and we can see how it responded to the chemotherapy. So, heaven forbid in the future, if we would have to treat again some time in the future, we could look at that and we can tell whether or not that patient responded to the therapy that we gave. So if they achieved a very good response with a particular therapy at that point in time they may respond to that treatment again later on. Likewise if there wasn t a good response with the particular therapy, that would be a therapy we would want to avoid. Just want to reiterate also to the second bullet point on this slide, that baseline tumor assessment for staging is really critical. Imaging studies and pathologic assessment of tumor tissue is essential prior to preoperative therapy because once it s taken off, we won t have access to it any longer. So it s very important that we get the baseline tumor assessments to really help us choose the right therapy for the patient. Now moving on to the notion of systemic treatment with chemotherapy, it s important to recognize that benefits of chemotherapy are not equivalent amongst all patients. We do know that some patients benefit more from others, and hence, the need to identify those patients most likely to benefit and those patients not likely to benefit, and hence, we need to avoid potentially causing harm or toxicity from the chemotherapy. The challenge again is identifying those most likely to benefit. And previously I had mentioned the use of --- of computerbased algorithms. This has made a huge difference in the clinic today but even - -- even with that, we --- there s still room for improvement. In addition, therefore, we are looking retrospectively at clinical trial data and doing meta-analyses on that data so that we can identify 10-year, 15-year, 20-year recurrence and survival. It is difficult given the varied disease amongst patients but the Early Breast Cancer Trialists Collaborative Group has done a phenomenal job at sifting through all this data multiple times and providing us with information to use in the clinic to make informed decisions along with our patients.

4 So there was a study published, the 2000 overview analysis, which looked at polychemotherapy versus no chemotherapy at all. So the notion of chemo or no chemo. And as you can see, 29,000, so a very large number of patients were randomized by the year 2000 to trials started by Now recognize you have to think about the chemotherapy that was given during this timeframe and it was mostly six or 12-month CMF, or cyclophosphamide, methotrexate, fluorouracilbased chemotherapy or six months of anthracycline-based chemotherapy. So at this time no taxanes or biologic agents were included in this particular review. Also there were few women over the age of 70. With this, though, significant improvements in the absolute risks of both recurrence and breast cancer mortality were shown. The recurrence had a 0.77 relative risk and the risk of mortality was a 0.83 relative risk, both significant. The absolute benefit from chemotherapy for both older and younger patients appeared most significant in ER-negative populations. So looking further into the polychemotherapy versus no chemotherapy data, this slide shows you data based on patients less than age 50 years or those aged 50 to 69 years on the right-hand side. This is a 15-year probability providing information on both the percentage of recurrence as well as the percentage of breast cancer mortality. And as you can see the absolute benefit was significant was significant in both age groups, in both recurrence, and breast cancer mortality. The graphs on this slide show the 15-year probabilities of death from breast cancer resulting from either treatment with adjuvant polychemotherapy or no adjuvant chemotherapy. Breast cancer mortality reported as a percentage is shown on the Y axis, and years post treatment, ranging from zero to 15, is recorded on the X axis. The control arms are depicted by a black line with black circles and the treatment arms are depicted by a blue line with squares. The graph on the left is patients who were aged less than 50 at the time of study entry and on the right are patients aged 50 to 69 years at study entry. In both, the differences between control and treatment are highly significant but the absolute benefit at 10 or 15 years appears to be approximately three times as great for younger versus older women. So if we look at the --- the timeframe for chemotherapy, single agent regimens were significantly less favorable than polychemotherapy or combination chemotherapy regimens for recurrence or mortality for 12 to 24 weeks. This is not surprising. We very much expect that multiple drugs will work better than single agents and this was exactly the case as we look through the meta-analysis of these trials. Again, looking at longer versus shorter duration regimens, and again, mostly with CMF-based regimens, there was little long-term gain with longer duration of

5 chemotherapy. So more is not necessarily better. The recurrence rates, the br -- - breast cancer death rate ratio, and the deaths without recurrence were not significantly different amongst the two durations of regimens. So now let s move into adjuvant cytotoxic chemotherapy. There have been a number of regimens evaluated in Phase III clinical trials and considered appropriate for use. There s not one magic regimen for all patients. It s very much a specific regimen based on those prognostic and predictive factors that I described earlier. There are multiple guidelines that I would also encourage you to access. The NCCN Guidelines for Breast Cancer, the St. Gallen International Breast Cancer Expert Panel Guidelines, and there s also a third guideline, the European Agency Guidelines, or the ESMO Guidelines. On this slide I have listed cytotoxic drugs that are used alone or in combination in the --- for adjuvant cytotoxic chemotherapy. These drugs fall into multiple classes the anthracyclines, the alkylating agents, antimetabolites, platinum analogs, and/or the taxanes. Let s first talk about the anthracyclines. These are a key class of cytotoxic chemotherapeutics in the adjuvant and neoadjuvant setting today. Again the Early Breast Cancer Trialists Cancer Group of 2000 Analysis confirmed a modest but highly significant benefit of anthracycline-based regimens for six months over a CMF regimen for six months. The absolute benefit at 15 years was 3.4% recurrence risk and a 3.3% risk reduction in mortality. And this was shown in both younger and older groups, also independent of hormone status. The taxanes are the most recent class of chemotherapy providing a backbone for adjuvant and neoadjuvant therapy today. Multiple large randomized trials have utilized both docetaxel as well as paclitaxel chemotherapy. And as you can see in multiple different regimens, sequential after anthracyclines, concurrent with the anthracyclines, and some trials even replacing taxanes with anthracyclines altogether. Dr. DeLaurentis and colleagues in Italy conducted a meta-analysis of randomized trials which evaluated the efficacy of incorporating the taxanes into anthracyclinebased regimens. Efficacy was defined by disease free survival and overall survival and whether the benefits are maintained. Thirteen randomized trials with nearly 23,000 patients were included in this meta-analysis. The addition of a taxane to an anthracycline-based regimen resulted in an absolute five year risk reduction of 5% for disease free survival or recurrence and 3% for overall survival or death. So to put this in the context, the Early Breast Cancer Trialists Collaborative Group meta-analysis showed an absolute risk reduction at five years of approximately 3% for both disease free and overall survival. This slide includes the meta curves of disease free survival, shown in curve A, as well as overall survival, shown in curve B. These were derived from stratified

6 pooling of the data. The X axis is time in years, and the Y axis is either disease free survival or overall survival. The control curve is depicted by the blue line whereas the taxanes curve is depicted by the yellow dotted lines. Based on these curves the estimated absolute risk reduction at five years gained by adding a taxane to anthracycline-based adjuvant regimens is approximately 5% for disease free survival and 3% for overall survival. Before moving to a discussion of biologic therapy it is important to recognize that the Early Breast Cancer Trialists Collaborative Group has published reviews of taxane trial results and published in this information in The Lancet This meta-analysis continues to show that polychemotherapy saves lives and that on average reduces breast cancer mortality by about one-third. Moving on to adjuvant biological therapy, it s currently standard of care for patients for HER2 positive breast cancer. This HER2 positive breast cancer occurs in approximately 20 to 30% of breast cancers and it s associated with increased tumor aggressiveness, increased rates of recurrence, and as then--- you would expect --- expect, increased rates of mortality. So HER2 testing is now considered standing --- standard --- [excuse me] --- in all newly diagnosed patients. Luckily we have treatment for this now through use of a monoclonal antibody against the HER2 receptor protein called trastuzumab. This drug was initially approved in the metastatic setting and then in 2006, received FDA approval in the adjuvant setting for those patients with node-positive or nodenegative and a tumor greater than or equal to 1 cm with the HER2 positive expression or amplification. Again studies have shown the benefit of adjuvant biologic therapy through metaanalysis of five clinical trials with almost 9800 patients. This was using trastuzumab with chemotherapy versus chemotherapy alone, and it showed significant survival benefits of the combination biologic therapy, trastuzumab, along with our standard chemotherapy. This was a disease free survival 0.62 relative risk, again, significant, and significant reductions, or rather --- [excuse me] --- improvements in overall survival with a 34% lower relative risk for death from any cause. This is a Forest plot for the disease free survival. Values lower than 1 indicate that trastuzumab has a beneficial effect when combined with chemotherapy. This lists the four main trials involving trastuzumab. And it shows that all of them showed a beneficial effect of the combination chemotherapy and trastuzumab as they are all well past or lower than 1. In summary, adjuvant therapy for HER2 breast cancer for management includes one year of adjuvant trastuzumab unless there s a contraindication. We have looked at using it shorter or longer and we haven t been able to change that oneyear timeframe. It seems that that appears to be the best information that we have at this time. This is given intravenously either weekly or every three weeks and generally it depends upon the other chemotherapy that we re given with it.

7 And we use it either way, whatever is most --- whatever is easiest for the patient to receive, whatever is most convenient for the patient. We use it concurrently with a taxane or after completion of chemotherapy but we, generally speaking right now, still do not use it along with anthracyclines. This is under study but for now we do not give it concomitantly, and that is because it also causes cardiotoxicity. It s a different mechanism than the anthracyclines but nonetheless, it could be additive and since this is in a curative setting we don t want to push the scale on the risk side over the benefit. So you re going to want to do thorough cardiac assessment with either an ECHO or a MUGA prior to the start of trastuzumab treatment. There is a black box warning with trastuzumab for subclinical and clinical cardiac failure. The highest absolute incidence is when given with an anthracycline. So, again, most importantly, have that cardiac assessment done prior to patients receiving cardiotoxic agents such as anthracyclines and/or the biologic therapy, trastuzumab. Now after trastuzumab was used in the adjuvant setting, it was moved to the neoadjuvant setting. And it was studied in multiple randomized trials. There was a US single institution study of 42 patients. These patients had Stage II to IIIA invasive disease that was not inflammatory. They received 24 weeks of trastuzumab plus neoadjuvant chemotherapy versus chemotherapy alone. There was then a second cohort of 22 additional patients treated with the trastuzumab plus neoadjuvant chemotherapy. Likewise there was a European study of 235 patients with locally advanced, and in this trial, inflammatory breast cancer patients. They received one year of trastuzumab in combination with chemotherapy versus neoadjuvant chemotherapy alone. The addition of trastuzumab to neoadjuvant chemotherapy based on those trials has been now been included in the NCCN and the St. Gallen guidelines for treatment of HER2 positive early stage breast cancer as standard of care. Subsequent trials have combined biologic therapy in the neoadjuvant setting with the newer drug, pertuzumab, to further increase the pcr rate compared to trastuzumab-based chemotherapy alone. So there have been two trials the Neo ALTTO, and NeoSphere trial. The one trial has used the addition of lapatinib which is an oral anti-2--- anti HER2 agent, and the second trial, the NeoSphere, has used pertuzumab which is a[n] intravenous anti-her2 therapy. On September 30 in 2013, the FDA granted accelerated appro --- approval --- [excuse me] --- of pertuzumab in the neoadjuvant setting in combination with trastuzumab and chemotherapy docetaxel, based on the results that we saw. This is specifically given for patients who have tumors that are greater than 2 cm or have node-positive disease and are locally advanced inflammatory or at an early stage. This approval established dual anti-her2 therapy in combination with chemotherapy as a standard of care. Approval of pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant setting has been based on two randomized multicenter open label

8 Phase II trials. These are patients with operable disease, tumor size of T2 to 4, with or without lymph node disease, good performance status of ECOG 0 or 1, and a good heart, those with ejection fraction greater than or equal to 55%. The NeoSphere trial included 417 patients. The primary endpoint of this study was the pathologic complete response rate in that breast tissue whereas the TRYPHAENA trial of 225 patients was really looking at the toxicity. And the primary objective of this trial was the cardiac tolerability during the neoadjuvant treatment. What we --- what has been established at this point for pertuzumab dosage and schedule is for the drug to be given every three weeks for three to six cycles as part of one of the following regimens for early stage breast cancer. The options are six preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel followed by three postoperative cycles of FEC, or fluorouracil, epirubicin, and cyclophosphamide. Secondly, three preoperative cycles of FEC followed by three cycles preoperatively of pertuzumab in combination with the docetaxel and trastuzumab. Or lastly, six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab. So those are the options at this point. There are other studies underway today looking at additional regimens but at this point, those are the --- the tree different options. There is insufficient evidence to recommend continued use of pertuzumab for more than six cycles for early stage breast cancer. So, again, based on that early data pertuzumab is used for six cycles only in either one of those three regimens described on the previous slide. Furthermore, concomitant administration of an anthracycline with pertuzumab is not currently recommended. Again this is under study but because of concerns with cardiotoxicity we are not administering them concomitantly. So, in summary, for pertuzumab, it received accelerated approval in the neoadjuvant setting based on improvement in the pathologic complete response rate. So not overall survival, disease free survival, but pathologic complete response rate. Therefore, continued approval for this indication will be contingent upon demonstrating improvement of disease free survival in a confirmatory trial, and this trial is called the APHINITY trial. So we re all awaiting the results of the APHINITY trial and hoping that this will continue to be positive and pertuzumab will remain standard of care. Pertuzumab in combination with trastuzumab and chemotherapy is also very tolerable. It s very similar in its side effect profile to trastuzumab along with standard chemotherapy and causes similar rates of cardiac dysfunction. There are ongoing studies of biologic therapy, as I mentioned previously, in the neoadjuvant setting as well as in the adjuvant setting. So in the neoadjuvant setting we re looking at cardiac safety and the long term benefits of pertuzumab, as I mentioned previously. We are trying to confirm the appropriate duration of pertuzumab and we re looking at sequential use of doxorubicin with pertuzumab

9 in addition to the epirubicin. In the adjuvant setting we re also combining pertuzumab with trastuzumab and chemotherapy. In the HER2 positive early stage breast neoadjuvant and adjuvant settings we are also testing adjuvant tres --- [excuse me] --- we re also testing adotrastuzumab emtansine as a single agent and in combination with pertuzumab. So again testing a single HER2 blockade as well as combination HER2 blockade with the pertuzumab. There are also investigational agents being tested, a dual EGFR and HER2 inhibitor such as neratinib as well as a P13K inhibitor. We are also studying the evaluation of predictive markers for identifying subgroups of patients who may benefit from HER2 targeted therapy alone without chemotherapy as well as those who may not benefit from any treatment. So in summary, breast cancer is a very diverse disease, it is a heterogenous disease, and not all treatment fits every patient. The benefits of systemic treatment with chemotherapy and biotherapy differ across patient subsets. The decision regarding use of chemotherapy and biotherapy is based on the estimated risk of recurrence as well as the benefits of therapy. Biologic features are now critically important to identify and play expanding roles in the treatment decisions for patients. Lastly, meta-analysis of randomized trials with adjuvant chemotherapy/biotherapy, demonstrate reductions in the odds of recurrence and death. This concludes the presentation. I look forward to hearing feedback and thank you for your participation.