Breast Cancer - Adjuvant and Metastatic

Transcription

1 Breast Cancer Update Live Clinical Investigator Think Tank: Proceedings from a CME Satellite Symposium at the Breast Cancer Symposium in San Francisco, California EDITOR A ND MODER ATOR Neil Love, MD FACULT Y Rowan T Chlebowski, MD, PhD Joyce O Shaughnessy, MD Mark D Pegram, MD Dennis J Slamon, MD, PhD George W Sledge Jr, MD Sandra M Swain, MD Eric P Winer, MD Edited Proceedings of the Think Tank and Interviews with Faculty from the publishers of CME Certified Subscribe to Podcasts or download MP3s of this program at BreastCancerUpdate.com/LiveThinkTank

2 Breast Cancer Update Live Clinical Investigator Think Tank: Proceedings from a CME Satellite Symposium at the Breast Cancer Symposium in San Francisco, California A Continuing Medical Education Audio Program S T A T E M E N T O F N E E D / T A R G E T A U D I E N C E Breast cancer is one of the most rapidly evolving fields in medical oncology. Published results from ongoing clinical trials lead to the continuous emergence of new therapeutic agents and changes in the indications for existing treatments. In order to offer optimal patient care including the option of clinical trial participation clinicians must be well informed of these advances. To bridge the gap between research and patient care, this program features one-on-one discussions with leading oncology investigators. By providing access to the latest research developments and expert perspectives, this CME program assists medical oncologists, hematologists and hematology-oncology fellows with the formulation of up-todate clinical management strategies. L E A R N I N G O B J E C T I V E S Evaluate the clinical implications of research data on breast cancer treatment, and apply this information to management strategies in the adjuvant and metastatic settings. Select adjuvant chemotherapy (anthracycline- versus nonanthracycline-containing regimens), hormonal therapy and/ or biologic therapy with trastuzumab, based on risk-benefit analyses and individual patient characteristics. Incorporate emerging data on biologic therapies into treatment algorithms for appropriately selected patients with metastatic breast cancer. Assess the contributory roles of hormone receptor and HER2 status on treatment selection and sequencing for metastatic breast cancer, and apply this information to patient care. Review the evidence on the evolving role of lifestyle modifications and their impact on the risk of breast cancer recurrence, and discuss this information with patients. Counsel appropriately selected patients about ongoing clinical trials in which they may wish to participate. P U R P O S E O F T H I S I S S U E The purpose of this program is to support the learning objectives by offering the perspectives of Drs Chlebowski, O Shaughnessy, Pegram, Slamon, Sledge, Swain and Winer on the integration of emerging clinical research data into the management of breast cancer. A C C R E D I T A T I O N S T A T E M E N T Research To Practice is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. C R E D I T D E S I G N A T I O N S T A T E M E N T Research To Practice designates this educational activity for a maximum of 4.25 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. H O W T O U S E T H I S C M E A C T I V I T Y This CME activity contains both audio and print components. To receive credit, the participant should listen to the CDs, review the monograph and complete the Post-test and Educational Assessment and Credit Form located in the back of this monograph or on our website. This monograph contains edited comments, clinical trial schemas, graphics and references that supplement the audio program. BreastCancerUpdate.com/LiveThinkTank includes an easy-to-use, interactive version of this monograph with links to relevant full-text articles, abstracts, trial information and other web resources indicated here in blue underlined text. This program is supported by educational grants from Genentech BioOncology and Sanofi-Aventis.

3 Breast Cancer Update Live Clinical Investigator Think Tank Proceedings from a CME Satellite Symposium at the Breast Cancer Symposium in San Francisco, California TABLE O F C ONTENTS 3 Adjuvant Chemotherapy for Patients with HER2-Negative Disease 6 Adjuvant Systemic Therapy for Patients with HER2-Positive Disease 8 Adjuvant Therapy for Elderly Patients with HER2-Positive Disease 9 Adjuvant Trial Evaluating Trastuzumab and/or Lapatinib in HER2- Positive Disease 11 Role of Bevacizumab for Patients with HER2-Negative Metastatic Disease 14 Adjuvant Trial Combining Bevacizumab with Trastuzumab 15 Optimizing First-Line Systemic Therapy for Patients with ER-Positive, HER2-Positive Metastatic Disease 18 POST-TEST 19 EDUCATIONAL ASSESSMENT AND CREDIT FORM If you would like to discontinue your complimentary subscription to Breast Cancer Update, please us at Info@ResearchToPractice.com, call us at (800) or fax us at (305) Please include your full name and address, and we will remove you from the mailing list.

4 C O N TENT VA LIDATION A ND D IS C LOSURE S Research To Practice is committed to providing its participants with high-quality, unbiased and state-ofthe-art education. We assess potential conflicts of interest with faculty, planners and managers of CME activities. Real or apparent conflicts of interest are identified and resolved through a conflict of interest resolution process. In addition, all activity content is reviewed by both a member of the Research To Practice scientific staff and an external, independent reviewer for fair balance, scientific objectivity of studies referenced and patient care recommendations. RESEARCH TO PRACTICE STAFF AND EXTERNAL REVIEWERS The following scientific staff and reviewers for Research To Practice reported real or apparent conflicts of interest for themselves (or their spouses/partners), which have been resolved through a conflict of interest resolution process: Aviva Asnis-Alibozek, PA-C, MPAS Salary: AstraZeneca Pharmaceuticals LP; Shareholder of: AstraZeneca Pharmaceuticals LP; Sally Bogert, RNC, WHCNP Shareholder of: Amgen Inc and Genentech BioOncology. All other Research To Practice staff and external reviewers: No real or apparent conflicts of interest to report. FACULTY The following faculty (and their spouses/partners) reported real or apparent conflicts of interest, which have been resolved through a conflict of interest resolution process: Dr Chlebowski Professor of Medicine, David Geffen School of Medicine at UCLA; Chief, Division of Medical Oncology and Hematology, Harbor-UCLA Medical Center, Torrance, California. Consulting Fees: AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, Pfizer Inc; Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation. Dr O Shaughnessy Co-Director, Breast Cancer Research Program, Baylor-Charles A Sammons Cancer Center, Texas Oncology, PA, US Oncology, Dallas, Texas. Consulting Fees: Biogen Idec, Bristol-Myers Squibb Company, Eisai Inc, Eli Lilly and Company, Genentech BioOncology, Genzyme Corporation, Novartis Pharmaceuticals Corporation, Ortho Biotech Products LP, Pfizer Inc; Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: Abraxis BioScience, Eli Lilly and Company, Sanofi-Aventis. Dr Pegram Professor of Medicine, University of Miami, Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida. Consulting Fees: Genentech BioOncology, GlaxoSmithKline, Pfizer Inc. Dr Slamon Professor of Medicine; Chief, Division of Hematology/Oncology; Director of Clinical/Translational Research, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California. Fees for Non-CME Services Received Directly from Commercial Interest or Their Agents: Genentech BioOncology, GlaxoSmithKline, Sanofi-Aventis; Ownership Interest: Amgen Inc, Pfizer Inc. Dr Sledge Ballve-Lantero Professor of Oncology; Professor of Medicine and Pathology, Melvin and Bren Simon Indiana University Cancer Center, Indianapolis, Indiana. Consulting Fees: Genentech BioOncology; Contracted Research: Sanofi-Aventis. Dr Swain Professor of Medicine, Georgetown University; Medical Director, Washington Cancer Institute, Washington Hospital Center, Washington, DC. Consulting Fees: Johnson & Johnson Pharmaceuticals, Roche Laboratories Inc; Travel for Clinical Investigator Meeting: Genentech BioOncology, Sanofi-Aventis. Dr Winer Director, Breast Oncology Center, Dana-Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts. No financial interests or affiliations to disclose. This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. Research To Practice does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. 2

5 Select Excerpts from the Discussion Adjuvant Chemotherapy for Patients with HER2-Negative Disease Track 2 DR LOVE: Dennis, what are your thoughts on the controversy regarding the use of anthracyclines for patients with either node-positive or nodenegative, HER2-negative disease? DR SLAMON: The US Oncology adjuvant trial evaluating patients with node-negative and node-positive disease demonstrated the superiority of the nonanthracycline-containing regimen over an anthracycline (Jones 2007; [1.1]). At UCLA, most of the investigators and clinicians, including myself, are using docetaxel and cyclophosphamide (TC) instead of AC. DR SWAIN: I feel comfortable not using an anthracycline for patients with node-negative disease. Perhaps it s not rational, but I make a distinction for patients with higher-risk disease. Furthermore, Mike Press and Soon Paik have demonstrated that TOPO II isn t overexpressed in patients with HER2-negative disease (Press 2007). Therefore, I don t believe we need the anthracyclines for these patients. However, for patients with HER2-negative, node-positive breast cancer, I admit I still use the anthracyclines. 1.1 Phase III Adjuvant Trial Comparing Docetaxel/Cyclophosphamide (TC) to Doxorubicin/Cyclophosphamide Six-year efficacy data TC AC Endpoint (n = 506) (n = 510) p-value Hazard ratio Disease-free survival (DFS) 81% 75% Overall survival (OS) 87% 82% Conclusions: With longer follow-up, TC was associated with improved DFS as well as OS compared to standard AC. TC should now be a standard non-anthracycline combination for early BC. In addition, TC was well-tolerated in older women without excessive toxicity compared to their younger counterparts, and may be preferable due to its lack of cardiotoxicity. SOURCE: Jones S et al. Presentation. San Antonio Breast Cancer Symposium 2007;Abstract 12. 3

6 DR LOVE: Eric, we ve seen some interesting data from MD Anderson and SEER in the last couple of years (Pinder 2007), and people are becoming concerned that the longer-term cardiac risk from anthracyclines may be greater than we believed. What are your thoughts? DR WINER: I don t believe we have a clear answer. I believe the risk of cardiac toxicity associated with anthracyclines will be higher for an older woman than for a younger woman and higher for someone who has some degree of cardiovascular disease. The real issue is whether a particular patient should receive chemotherapy. The next question is which chemotherapy she should receive. With regard to Sandy s point, the smaller the potential benefit of chemotherapy, the less you have to worry about losing some benefit by skipping an anthracycline. I believe it s likely that we will be using far less anthracyclinebased therapy a few years from now. The real quandary is when we ll be ready to make that move on a wholesale basis. DR LOVE: George, what s your take on this? DR SLEDGE: I believe Eric is correct. It s highly likely that we ll be using fewer anthracyclines five years from now. It s also highly likely that we ll be using less chemotherapy five years from now, as we become better at predicting who doesn t receive marginal benefit from chemotherapy in that postmenopausal, hormone receptor-positive setting. Even among patients with node-positive disease, I suspect we ll be using less chemotherapy. I m not uncomfortable with the idea that we ll eliminate anthracyclines. I m not comfortable with what we will use to replace the anthracyclines because the US Oncology trial, which is a good trial, is nevertheless a single trial. It s somewhat smaller than our current generation of trials in the adjuvant setting. A reasonable question would be, if a patient came in with a 5.5-cm, Clinical Use of Adjuvant Anthracyclines for Patients with HER2-Negative Breast Cancer I suspect that the anthracycline days are probably numbered and that Dr Slamon is correct in his view that we do not need to use them in the adjuvant setting for HER2-positive or -negative breast cancer. One can make very compelling arguments supporting his view, going all the way back to NSABP-B-11 and in looking at the Canadian studies comparing CMF versus CEF. The only question is, do we now need a prospective randomized trial to confirm it? I know the cooperative groups are considering a TAC-versus-TC-type trial as a follow-on to B-38, for example, in patients with HER2-negative disease. If we need a prospective trial to prove it, so be it. However, we probably have enough evidence now from retrospective studies because there are so many of them and essentially all of them show an association. I believe we probably can exclude anthracyclines while safely maintaining efficacy and improving the therapeutic index for all breast cancer patients. Mark D Pegram, MD 4

7 triple-negative tumor that had nine positive lymph nodes, would you be comfortable with four cycles of anything in that setting? We still have a lot of work to do to determine not necessarily what we need to eliminate but rather what we need to use. Track 14 DR LOVE: Mark, how do you approach the selection of chemotherapy for the patient with node-negative, HER2-negative early breast cancer? DR PEGRAM: You must have a balanced discussion with the patient and evaluate her comorbid medical conditions, et cetera. We have nice data comparing nonanthracycline regimens to anthracycline regimens, and clearly the nonanthracycline regimens are preferable. It boils down to a patient s relative risk and which regimen she s likely to tolerate. I use a lot of TC for patients with node-negative disease. It s tolerable, but our patients at UCLA tend to be younger. Moreover, we participated in the Phase III trials of TAC versus FAC in the metastatic and the adjuvant settings, so we have quite a bit of experience with docetaxel-based regimens at our institution. I feel comfortable using TC. DR SLAMON: It s clear that physicians are using TC now. The benefits are the same for patients with higher-risk disease as for those with node-negative breast cancer. TC is easy to administer, and the patients are finished with their chemotherapy in 12 weeks. DR WINER: Does it give you pause that the ECOG trial didn t show any benefit for doxorubicin/docetaxel (AT) over AC (Goldstein 2005), yet you re comfortable concluding that TC is better than AC? I ve struggled with that. DR O SHAUGHNESSY: In ECOG-E2197 evaluating AC versus AT for patients with zero to three positive nodes the disease-free and overall survival curves were absolutely superimposable. Laurie Goldstein presented an exploratory analysis based on hormone receptor status, and among the patients with ER-negative, PR-negative tumors, the AT was trending toward being better. In the ER-positive, PR-positive subset, AC was trending toward being better than AT. Those trends may have balanced each other out. In the TC regimen, the cyclophosphamide may have some benefit with regard to ovarian suppression in the premenopausal and perimenopausal patients. Data for taxanes in the patients with hormone receptor-negative disease are emerging from the subset analyses. I believe TC provides the best of both worlds that s how I interpret it. DR SLEDGE: Let me suggest an alternative hypothesis. I ve wondered whether or not we ve been missing something with TC, and that s the possibility of 5

8 synergy. The trials of TAC versus FAC and TC versus AC (Jones 2007) were both positive. The working assumption has been that docetaxel is a better drug. The other possibility is that TC is a better combination. One way of explaining the conundrum that Eric raised is that TC is a synergistic combination and there is something special about the combination, rather than the substitution of docetaxel for doxorubicin. DR CHLEBOWSKI: In the US Oncology trial, the dose of docetaxel was 75 mg/m 2, compared to 60 mg/m 2 in the AT regimen of E2197. If you like the dose-response story, that might be another explanation. DR LOVE: Joyce, can you comment on the tolerability of the TC regimen? DR O SHAUGHNESSY: TC is well tolerated in terms of how patients feel. We are receiving some comments from the people participating in the trial that a CBC at day 10 may indicate some paper toxicity for neutropenia. We will be watching febrile neutropenia rates carefully because growth factors were optional in the trial. We ll be checking after the first several hundred patients on each arm, but right now we don t have any data to suggest that prophylactic pegfilgrastim is necessary, because the febrile neutropenia rate in the clinical trial was only five percent. Adjuvant Systemic Therapy for Patients with HER2-Positive Disease Tracks 28, 30 DR LOVE: Eric, how do you approach chemotherapy selection in combination with adjuvant trastuzumab? DR WINER: A few regimens have shown benefit in the adjuvant trials. The choices include an anthracycline followed by a taxane with trastuzumab, or TCH. We tend to administer more anthracycline followed by trastuzumab and a taxane. I don t know whether that will be the case in a year or two or three, pending further follow-up on the BCIRG 006 trial. DR LOVE: George, how are you approaching this question in the clinical setting? DR SLEDGE: I use a lot more TCH now than I used a year ago. The followup issue doesn t bother me as much as some. I am comfortable using TCH and use it relatively often in my practice. DR SWAIN: I would definitely use TCH. I used it even before the results were out, for a patient with inflammatory breast cancer in particular. But I also was not too concerned about the follow-up because the data became stronger with the second interim analysis. 6

9 DR LOVE: Sandra, I understand that the CIRG and the NSABP are collaborating on the BETH trial, which evaluates TCH with or without bevacizumab in the adjuvant setting (1.2). What factors led to TCH being chosen for this trial? DR SWAIN: I believe the CIRG and the NSABP were convinced by the BCIRG 006 data. Also, as Vice Chair of the NSABP, I was strongly in favor of a nonanthracycline-containing regimen because of all the issues already discussed relating to cardiac toxicity. 1.2 BETH Trial: Adjuvant Chemotherapy and Trastuzumab with or without Bevacizumab Eligibility Node-positive or high-risk, node-negative breast cancer HER2-positive by central testing R Chemotherapy* q3wk x 6 + trastuzumab x 1 year Chemotherapy* q3wk x 6 + trastuzumab x 1 year + bevacizumab x 1 year * For NSABP and CIRG investigators, chemotherapy = docetaxel/carboplatin For independent investigators, chemotherapy = docetaxel x 3 FEC x 3 (targeted therapy held during FEC) SOURCES: Slamon D. CIRG ECCO-14 Satellite Symposium: The Art of Oncology, September 26, No abstract available; Interview, Charles E Geyer Jr, MD, November Clinical Trial of Adjuvant Chemotherapy and Trastuzumab with or without Bevacizumab We are very excited about the adjuvant BETH trial for HER2-positive breast cancer, which includes patients with negative nodes. For participating NSABP and CIRG investigators, patients will be randomly assigned to docetaxel/carboplatin/trastuzumab with or without bevacizumab (1.2). The CIRG and NSABP are both convinced that we don t need anthracyclines in these cases. However, for independent Australian or European investigators, the chemotherapy will be anthracycline based, specifically docetaxel followed by FEC plus trastuzumab with or without bevacizumab (Geyer 2007). Trastuzumab will not be given while patients are receiving FEC. Sandra M Swain, MD 7

10 Adjuvant Therapy for Elderly Patients with HER2-Positive Disease Track 7 DR LOVE: Dennis, do you feel that trastuzumab, either alone or with endocrine therapy, is a reasonable clinical approach for elderly patients with ER-positive, HER2-positive tumors that are small and node-negative? DR SLAMON: I have used that regimen for patients when I ve been concerned about the toxicity associated with chemotherapy, being aware of the fact that good data are showing that chronologic age isn t the factor it has to be performance status. I believe the study that Chuck Vogel led showed convincingly that trastuzumab monotherapy can be effective in a patient population with metastatic disease, and not even restricted to the older patient population. DR LOVE: Let me ask you about an 86-year-old patient we discussed in one of our Meet The Professors sessions. The patient had HER2-positive, ER-positive disease with five positive nodes, had some Parkinson s disease and was frail. The oncologist was concerned about a taxane. Would you consider administering chemotherapy to this patient? DR SWAIN: If she were especially frail, I would administer an aromatase inhibitor and trastuzumab. If she were in good health, I wouldn t administer an anthracycline, not at age 86, because I m sure she has the usual comorbidities of that age group. I would use something that s not as data driven, such as weekly paclitaxel. Clinical Use of Adjuvant Trastuzumab for Elderly or Frail Patients I have treated healthy older patients, even women with T1 tumors, with the combination of trastuzumab and chemotherapy. As for adjuvant trastuzumab alone in the elderly, I can only think of one case an 88-year-old woman with a node-positive, HER2-positive cancer, who I treated with capecitabine and trastuzumab, but she didn t tolerate the capecitabine, so I just used an aromatase inhibitor and trastuzumab. I am currently treating a patient who is in her late seventies with a favorable cancer T1N0, ER-positive with weekly paclitaxel and trastuzumab and she is doing fine. As patients get older, they are delicately balanced, so we re increasingly concerned about harming them and I won t use doublet chemotherapy with trastuzumab. I haven t tried nab paclitaxel with trastuzumab in the adjuvant setting, but it s a thought in patients who are diabetic or weak in the muscles, where steroid premedication is a problem. Joyce O Shaughnessy, MD 8

11 Adjuvant Trial Evaluating Trastuzumab and/or Lapatinib in HER2-Positive Disease Track 31 DR LOVE: Eric, the ALTTO trial is evaluating adjuvant chemotherapy followed by trastuzumab versus lapatinib versus the combination or the sequence (1.3). What are your thoughts about the combination and about the fact that some patients will not receive trastuzumab on this study? DR WINER: In terms of the combination, what is known comes mostly from a trial at Indiana University evaluating the combination in a Phase I setting (Storniolo 2005). The combination was tolerable, although there was some suggestion that more responses occurred than had been recorded with singleagent lapatinib, but that s comparing across trials. I believe it s reasonable to have a lapatinib-only arm, but patients should not receive lapatinib alone outside of a trial. I believe that we all felt more comfortable after the results were presented at ASCO this year on administering lapatinib in combination with paclitaxel to patients who were thought 1.3 Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) Trial Protocol ID: BIG 2-06; Target Accrual: 8,000 Eligibility HER2-positive breast cancer In Design 1, patients will complete all (neo)adjuvant chemotherapy prior to administration of targeted therapy. In Design 2, patients will receive weekly paclitaxel concurrently with targeted therapy after any anthracycline-based (neo)adjuvant chemotherapy. Trastuzumab Trastuzumab q3wk x 52 weeks Lapatinib R Lapatinib daily x 52 weeks Trastuzumab lapatinib Trastuzumab qwk x 12 six-week washout lapatinib daily x 34 weeks Lapatinib + trastuzumab [Lapatinib daily + trastuzumab q3wk] x 52 weeks SOURCES: 9

12 ALTTO Trial of Trastuzumab, Lapatinib or the Combination In 2006, I coauthored a paper with Konecny, published in Cancer Research, where we tested the combination of lapatinib and trastuzumab in cell-lined models in the laboratory, and we found strong synergism between these two agents (Konecny 2006). We were surprised because we expected to find that they were antagonistic. In fact, we conducted the experiment to prove that HER2 was the real target of lapatinib and not EGF receptor, because if it s the real target, then it should compete for any other HER2-directed therapy like trastuzumab. However, we observed exactly the opposite, and so on the basis of that observation we ve now finished a Phase I dose-escalation trial and established a recommended Phase II dose. The results from the dose-escalation trial are currently in press and will show that, to our surprise, I believe it was six out of the first 26 patients responded to the combination of lapatinib plus trastuzumab, and all six of those patients had had prior treatment failure on trastuzumab. I believe the combination will prove to be active, and the question is whether it s more active than either single agent, and the ALTTO trial will answer that. Mark D Pegram, MD to have HER2-negative disease (Di Leo 2007). The addition of lapatinib led to a similar improvement in outcome to that seen with trastuzumab. DR LOVE: Joyce, how would you feel about putting a patient with multiple positive lymph nodes on the ALTTO trial (1.3)? DR O SHAUGHNESSY: I would be comfortable supporting the ALTTO trial. The paclitaxel data that Eric referred to were impressive. SELECT PUBLICATIONS Di Leo A et al. Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients with metastatic breast cancer: A phase III randomized, double-blind study of 580 patients. Proc ASCO 2007;Abstract Goldstein L et al. E2197: Phase III AT (doxorubicin/docetaxel) vs AC (doxorubicin/cyclophosphamide) in the adjuvant treatment of node positive and high risk node negative breast cancer. Proc ASCO 2005;Abstract 512. Jones S et al. Extended follow-up and analysis by age of the US Oncology adjuvant trial 9735: Docetaxel/cyclophosphamide is associated with an overall survival benefit compared to doxorubicin/cyclophosphamide and is well-tolerated in women 65 or older. Presentation. San Antonio Breast Cancer Symposium 2007;Abstract 12. Pinder MC et al. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007;25(25): Abstract Press MF et al. Alteration of topoisomerase II-alpha gene in human breast cancer and its association with responsiveness to anthracycline-based chemotherapy. Poster. Proc ASCO 2007;Abstract 524. Slamon D. What s next for the BCIRG? CIRG ECCO-14 Satellite Symposium: The Art of Oncology No abstract available Storniolo AM et al. A phase I, open-label study of lapatinib (GW572016) plus trastuzumab: A clinically active regimen. Proc ASCO 2005;Abstract

13 Select Excerpts from the Discussion Role of Bevacizumab for Patients with HER2-Negative Metastatic Disease Track 17 DR LOVE: Eric, can you comment on how you approach the patient with triple-negative breast cancer who develops cancer relapse soon after receiving adjuvant chemotherapy? DR WINER: Typically, I would administer bevacizumab and weekly paclitaxel, with the exception of a patient who had a particularly short disease-free interval (less than one year) and had received a taxane in the adjuvant setting. In that situation, we don t have a clear answer, and I would be inclined to use another chemotherapeutic agent with bevacizumab. I would pick an agent for which we have toxicity data because from an efficacy standpoint, I don t believe we can answer the question. DR SWAIN: I would use paclitaxel and bevacizumab. The patients in ECOG- E2100 who had received adjuvant taxanes were required to have had a diseasefree interval of at least 12 months, and they derived a significant benefit from paclitaxel and bevacizumab (Miller 2007; [2.1]). DR SLEDGE: Approximately one in five patients entering the trial had received an adjuvant taxane one year or more in the past. The hazard ratio for those patients was the best hazard ratio of any subgroup in the forest plot, almost as if bevacizumab in that setting is at least partially reversing taxane resistance. DR LOVE: George, what is your algorithm for first-line therapy for the patient with progressive, hormone-insensitive, indolent disease? DR SLEDGE: I believe this is a case in which you sit down and discuss the factors with the patient. Eleven-month progression-free survival is pretty good in the metastatic setting. I would add that I do not see a whole lot of evidence that we should be using bevacizumab further along. We have no evidence for benefit with this agent for anything other than front-line metastatic disease in breast cancer. If I were going to use bevacizumab for a patient, I would use it up front. Track 20 DR LOVE: Joyce, can you discuss the use of bevacizumab as second- or third-line therapy for metastatic disease? 11

14 2.1 ECOG-E2100: A Phase III Randomized Trial of Paclitaxel with or without Bevacizumab as First-Line Therapy for Patients with Locally Recurrent or Metastatic Breast Cancer Efficacy data (N = 673) Paclitaxel Paclitaxel Hazard Parameter + bevacizumab alone ratio p-value Objective response rate All patients 36.9% 21.2% NR <0.001 Patients with measurable 49.2% 25.2% NR <0.001 disease at baseline Median progression-free 11.8 months 5.9 months 0.60* <0.001 survival Median overall survival 26.7 months 25.2 months NR = not reported * Hazard ratio for disease progression SOURCE: Miller K et al. N Engl J Med 2007;357(26): Abstract Bevacizumab for the Treatment of Triple-Negative Breast Cancer Bevacizumab looks very promising for patients with triple-negative breast cancer. In the subset analysis of the E2100 trial comparing the weekly paclitaxel with or without bevacizumab there was a very large improvement in progression-free survival with the combination (Miller 2007). In patients with triple-negative disease, the point estimate is approximately 0.6 and the progression-free survival improved from approximately five months to 11, so that s very encouraging. In fact, I understand that a registrational adjuvant trial will be conducted in Europe in which physicians will choose the chemotherapy to be used with or without bevacizumab, specifically for patients with triple-negative breast cancer. Joyce O Shaughnessy, MD DR O SHAUGHNESSY: In Kathy Miller s trial of capecitabine with or without bevacizumab for patients previously treated for metastatic disease, the response rate was higher with the combination (Miller 2005), but not progression-free survival. The concern I ve always had about these later-line trials, though, is that when your endpoint is to change the median progression-free survival, you have to positively affect 50 percent or more of your patients because if only one third of your patients are benefiting, you won t change your median. The other data that I find especially interesting are Mark Pegram s with trastuzumab-pretreated patients. I agree we have to wait for the RIBBON 12

15 2 trial data to be sure, but I believe that at least some data support the use of later-line bevacizumab. DR LOVE: Eric, what about the issue of how one defines first and second line? DR WINER: I believe we are a little rigid about this because, depending on what someone received in the adjuvant setting, patients in the second-line metastatic setting may have received far less therapy than patients who are being treated in the first-line setting. I agree with George and would be inclined to use bevacizumab earlier rather than later. That said, for the patient who decides to take capecitabine at the first line in the metastatic setting, I am not uncomfortable using paclitaxel/ bevacizumab as the second-line regimen, but I stop it there. I want to make one other point regarding median time to progression. Median time to progression is a surrogate for the whole curve, so when you obtain a p-value for that Kaplan-Meier curve, it s on the entire curve it s not only about the median. It s convenient to talk about the median, but sometimes you can have a significant p-value and no difference in the median. Track 21 DR LOVE: George, where are we heading with bevacizumab dosing? DR SLEDGE: The dose of bevacizumab is controversial primarily because of the issue of cost. We chose the dose of bevacizumab to use in our Phase III trial based on a Phase II trial in which we evaluated three dose levels (Cobleigh 2003). We began with three milligrams per kilogram, followed by 10 milligrams per kilogram and then 20 milligrams per kilogram. We noted a slightly higher response rate at 10 compared to three. The 20-mg/kg dose produced horrendous migraines. That is the dose-limiting toxicity of bevacizumab. From the Phase I trials, we know that doses as low as one milligram per kilogram are pretty effective at Hoovering up all of the circulating VEGF so who knows? Maybe there s a difference intratumorally in the tumor microenvironment. We were able to measure VEGF only at the circulating level and there you eliminate it all at a fairly low dose. DR LOVE: What about side effects and toxicity with different doses? DR SLEDGE: I believe there s probably a range in which you re not going to discern much difference. More toxicity occurs at a certain level not only with bevacizumab but also with a fair number of smallmolecule receptor tyrosine kinase inhibitors at which migraine and hypertension rates begin to increase. 13

16 Adjuvant Trial Combining Bevacizumab with Trastuzumab Track 30 DR LOVE: Mark, what do we know in terms of trials evaluating trastuzumab and bevacizumab together, as is being tested in the BETH trial? DR PEGRAM: An interim analysis of our ongoing Phase II trial of bevacizumab in combination with trastuzumab as first-line treatment for HER2- positive metastatic breast cancer was presented previously at San Antonio (Pegram 2006; [2.2]). Among the 37 evaluable patients, the overall response rate was 54 percent, which we thought was a fairly robust efficacy signal for an all-biologic combination. Some concern arose regarding cardiac safety. One patient receiving the combination developed congestive heart failure, and a number of asymptomatic declines in ejection fraction were recorded among those 37 patients. However, I hasten to add that an ascertainment bias is possible in this data set in that it represents the most heavily screened patient population treated with trastuzumab to date. We evaluated ejection fractions at baseline and closely each month thereafter. Cardiac safety will continue to be monitored closely as the project moves forward into the randomized trials. The BETH trial will now evaluate this in the adjuvant setting (1.2, page 7). 2.2 Phase II Study of Bevacizumab (B) and Trastuzumab (T) for Women with Relapsed or Metastatic HER2-Positive Breast Cancer (BC) Interim efficacy data (N = 37)* Number Number Parameter Percent of patients (confirmed) Overall response rate 54.1% Not reported Not reported Complete response 2.7% 1 1 Partial response 51.4% Stable disease 29.7% 11 NA * Investigator reported objective clinical responses (WHO criteria) among patients with at least one response assessment Discussion: This is the first phase II trial of two humanized antibodies given in combination to human subjects. T + B is clinically feasible and active in HER2-amplified recurrent or metastatic BC. These data support the use of combination therapies directed against HER2 and VEGF for treatment of BC with HER2 alteration. SOURCE: Pegram M et al. San Antonio Breast Cancer Symposium 2006;Abstract

17 Optimizing First-Line Systemic Therapy for Patients with ER-Positive, HER2-Positive Metastatic Disease Tracks DR LOVE: What do you think about the data from the TAnDEM trial, comparing anastrozole with or without trastuzumab for patients with HER2-positive, hormone receptor-positive breast cancer? DR PEGRAM: The TAnDEM trial data support the hypothesis that crosstalk perturbation may be efficacious. It certainly met its primary endpoints in terms of demonstrating efficacy (2.3). However, it did not prove the hypothesis because the trial had no trastuzumab-alone control arm. That s the big question with regard to TAnDEM in terms of the science: Would it have demonstrated superiority over a trastuzumab-alone control arm? The result with trastuzumab and an aromatase inhibitor was not particularly impressive in this series, either. DR LOVE: Joyce, how do you approach first-line therapy for a patient who has hormone receptor-positive, HER2-positive breast cancer, assuming she has received no prior anti-her2 therapy? DR O SHAUGHNESSY: I usually administer endocrine therapy first, and some patients fare extremely well for a long time. 2.3 TAnDEM: A Randomized Trial Comparing Anastrozole with or without Trastuzumab for Patients with HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (N = 208) Anastrozole + Parameter Anastrozole trastuzumab p-value Median progression-free survival 2.4 months 4.8 months (95% CI: ) (95% CI: ) Partial response rate 6.8% 20.3% Clinical benefit rate 27.9% 42.7% Median overall survival 23.9 months 28.5 months (95% CI: ) (95% CI: ) Median overall survival for 32.1 months 41.9 months patients without liver metastasis* (95% CI: ) (95% CI: ) * Unplanned subgroup analysis SOURCE: Mackey JR et al. San Antonio Breast Cancer Symposium 2006;Abstract 3. 15

18 I go back to Kent Osborne s paper in the Journal of the National Cancer Institute a few years ago, which reported retrospectively evaluating patients with HER2- positive versus HER2-negative disease with regard to tamoxifen benefit in the adjuvant setting based on ER-positive, PR-positive versus ER-positive, PRnegative status (Arpino 2005). The patients with ER-positive, PR-positive, HER2-positive breast cancer did receive some benefit from tamoxifen in the adjuvant setting, so I believe it s not an absolute that these patients will not receive some benefit, and I initially use endocrine therapy alone. DR LOVE: Dennis, what about the patient who received prior adjuvant trastuzumab? How do you approach that decision in terms of anti-her2 therapy Combining Trastuzumab with Endocrine Therapy for Hormone Receptor-Positive, HER2-Positive Disease Generally speaking, most patients in the HER2-positive setting do not have disease that is terribly sensitive to endocrine therapy. We know that from historical experience as well as from the control arm data of the TAnDEM study, where the median time to disease progression among women on the anastrozole-alone arm was 2.4 months. In my mind, TAnDEM really gives us permission to use either anastrozole alone or, for that matter, another hormonal therapy, plus trastuzumab. I believe the take-home message is that adding trastuzumab to anastrozole increased the response rate by a small amount, doubled the time to progression but doubled it from 2.4 months to 4.8 months. My own interpretation is that it would suggest that there s some amount of additivity in terms of the effect. There was no survival advantage, although the study wasn t powered to look for a survival advantage. If I saw a 65-year-old woman with early, asymptomatic metastases, I would more commonly treat her with anastrozole or another hormonal therapy alone, saving trastuzumab to give probably with chemotherapy. I would watch her closely and tell her that there s a small chance she will be on that hormonal therapy for a long period of time. I don t object to the combination of hormonal therapy plus trastuzumab, but obviously it s a little bit more cumbersome. It involves an intravenous therapy. One of the beauties of hormonal therapy is that it often keeps the patient out of the infusion room. Eric P Winer, MD The TAnDEM trial demonstrated that women with HER2-positive and ER-positive breast cancer were not terribly responsive to the aromatase inhibitor and that patients who received both trastuzumab and the endocrine agent did better although the effect is right in the ballpark of what we see with trastuzumab alone (Mackey 2006). These results did not surprise me. Rather, what surprised me was that people didn t expect these data. If there had been a third arm consisting of chemotherapy plus trastuzumab, I suspect that combination may have been superior, but I believe the right third arm would have been trastuzumab alone to determine what signal that would give us. Dennis J Slamon, MD, PhD 16

19 on relapse, and how do you factor in the time since the last trastuzumab administration? DR SLAMON: If the patient has blown through a trastuzumab regimen and relapsed quickly, within a year after receiving adjuvant trastuzumab, I consider an alternative targeting agent, such as lapatinib. If it s been a year, 18 months or more, I consider using trastuzumab with another therapeutic agent vinorelbine or gemcitabine. A number of agents can be used while still using trastuzumab. First-Line Therapy for Patients Who Relapse After Receiving Adjuvant Trastuzumab Thankfully, I have yet to see many patients who have relapsed after adjuvant trastuzumab, but I believe we know from the clinical trial results that there will be such patients. Trastuzumab doesn t prevent all recurrences. It reduces them by 50 percent across the board in the clinical trials. The way I will evaluate those patients will depend very much on the length of time that has elapsed since they have received trastuzumab or trastuzumab and chemotherapy. A patient who develops a recurrence while on or soon after receiving a combination of adjuvant trastuzumab and chemotherapy, in my mind, is really no different from the patient who, in the metastatic setting, has received a first-line regimen of trastuzumab and paclitaxel or docetaxel, and you re considering a second-line regimen. Capecitabine and lapatinib would clearly be my choice in patients who relapse during adjuvant therapy. For a patient who relapses three years after receiving adjuvant trastuzumab, I would probably re-treat with trastuzumab. At this point the patient s disease is likely to be sensitive to trastuzumab, so I would not approach her much differently than I would approach the patient who presents with de novo HER2-positive disease. Eric P Winer, MD SELECT PUBLICATIONS Arpino G et al. Estrogen receptor-positive, progesterone receptor-negative breast cancer: Association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 2005;97(17): Abstract Cobleigh MA et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003;30(5 Suppl 16): Abstract Mackey JR et al. Trastuzumab prolongs progression-free survival in hormone-dependent and HER2-positive metastatic breast cancer. San Antonio Breast Cancer Symposium 2006;Abstract 3. Miller K et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357(26): Abstract Miller KD et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005;23(4): Abstract Pegram M et al. Phase II combined biological therapy targeting the HER2 protooncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer. San Antonio Breast Cancer Symposium 2006;Abstract

20 POST-TEST Breast Cancer Update Live Clinical Investigator Think Tank: Proceedings from a CME Satellite Symposium at the Breast Cancer Symposium in San Francisco, California QUESTIONS ( PLE ASE CIRCLE ANSWER) : 1. The Phase III adjuvant trial comparing docetaxel/cyclophosphamide (TC) to doxorubicin/cyclophosphamide (AC) for women with early-stage breast cancer demonstrated improved DFS and OS with. a. AC b. TC 2. Results of research conducted by Drs Press and Paik indicate that topoisomerase II (TOPO II) is overexpressed in patients with HER2-negative breast cancer. a. True b. False 3. The ECOG-E2100 Phase III randomized study of paclitaxel with or without bevacizumab showed improvements in response rate, median overall survival and median progression-free survival with the combination. a. True b. False 4. In the TAnDEM randomized trial evaluating anastrozole with or without trastuzumab, the median progressionfree survival with anastrozole and trastuzumab versus anastrozole alone was approximately. a. Equal b. Doubled c. Tripled 5. Dr Mark Pegram and colleagues Phase II study of combined biologic therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab and bevacizumab as first-line treatment of HER2-amplified breast cancer showed an overall response rate of. a. Five percent b. 36 percent c. 54 percent 6. The ALTTO trial will include a randomization arm with no trastuzumab treatment. a. True b. False 7. The NSABP-CIRG version of the BETH trial will evaluate docetaxel/ carboplatin/trastuzumab with or without bevacizumab. a. True b. False 8. Dr George Sledge and colleagues Phase II trial evaluating different doses of bevacizumab found the dose-limiting toxicity of this drug to be. a. Fever b. Migraines c. Nausea 9. In the Phase III ECOG-E2197 trial evaluating AC versus AT in the adjuvant treatment of node-positive and high-risk, node-negative breast cancer, AT showed superiority over AC. a. True b. False 10. According to ECOG-E2100, paclitaxel and bevacizumab significantly prolong disease-free survival compared to as initial chemotherapy for patients with metastatic breast cancer. a. Paclitaxel alone b. Paclitaxel and capecitabine c. Nab paclitaxel and bevacizumab Post-test answer key: 1b, 2b, 3a, 4b, 5c, 6a, 7a, 8b, 9b, 10a 18

21 EDUCATIONAL ASSESSMENT AND CREDIT FORM Breast Cancer Update Live Clinical Investigator Think Tank: Proceedings from a CME Satellite Symposium at the Breast Cancer Symposium in San Francisco, California Research To Practice is committed to providing valuable continuing education for oncology clinicians, and your input is critical to helping us achieve this important goal. Please take the time to assess the activity you just completed, with the assurance that your answers and suggestions are strictly confidential. PART ONE Please tell us about your experience with this educational activity BEFORE completion of this activity, how would you characterize your level of knowledge on the following topics? 4 = Expert 3 = Above average 2 = Competent 1 = Insufficient Adjuvant chemotherapy for patients with HER2-negative breast cancer Adjuvant systemic therapy for patients with HER2-positive disease Role of bevacizumab for patients with HER2-negative metastatic disease Optimizing first-line systemic therapy for patients with ER-positive, HER2-positive metastatic disease Was the activity evidence based, fair, balanced and free from commercial bias? Yes No If no, please explain: Will this activity help you improve patient care? Yes No Not applicable If no, please explain: Did the activity meet your educational needs and expectations? Yes No If no, please explain: Please respond to the following LEARNER statements by circling the appropriate selection: 4 = Yes 3 = Will consider 2 = No 1 = Already doing N/M = Learning objective not met N/A = Not applicable As a result of this activity, I will: Evaluate the clinical implications of research data on breast cancer treatment, and apply this information to management strategies in the adjuvant and metastatic settings N/M N/A Select adjuvant chemotherapy (anthracycline- versus nonanthracyclinecontaining regimens), hormonal therapy and/or biologic therapy with trastuzumab, based on risk-benefit analyses and individual patient characteristics N/M N/A Incorporate emerging data on biologic therapies into treatment algorithms for appropriately selected patients with metastatic breast cancer N/M N/A Assess the contributory roles of hormone receptor and HER2 status on treatment selection and sequencing for metastatic breast cancer, and apply this information to patient care N/M N/A Review the evidence on the evolving role of lifestyle modifications and their impact on the risk of breast cancer recurrence, and discuss this information with patients N/M N/A Counsel appropriately selected patients about ongoing clinical trials in which they may wish to participate N/M N/A What other practice changes will you make or consider making as a result of this activity? AFTER completion of this activity, how would you characterize your level of knowledge on the following topics? 4 = Expert 3 = Above average 2 = Competent 1 = Insufficient Adjuvant chemotherapy for patients with HER2-negative breast cancer Adjuvant systemic therapy for patients with HER2-positive disease Role of bevacizumab for patients with HER2-negative metastatic disease Optimizing first-line systemic therapy for patients with ER-positive, HER2-positive metastatic disease