Expert Interview SABCS 2007: Highlights and Clinical Implications for Metastatic

Expert Interview SABCS 2007: Highlights and Clinical Implications for Metastatic Breast Cancer

Expert Interview SABCS 2007: Highlights and Clinical Implications for Metastatic Breast Cancer December 13-16, 2007San Antonio, TexasLee Schwartzberg, MD, Director, The West Clinic, Memphis, TNWelcome to an Expert Interview from the 2007 San Antonio Breast Cancer Symposium: Highlights and Clinical Implications for Metastatic Breast Cancer.

Your faculty for this presentation will be Dr.  Lee Schwartzberg from the West Clinic in Memphis, Tennessee.

The following is a Continuing Medical Education (CME) activity, through joint sponsorship of Creative Educational Concepts, Inc. and OncoEd, Inc.  You may receive a certificate of completion for AMA PRA Category 1 Credits. Please refer to the OncoEd website at to participate in this CME activity online, and for the Learning Objectives, Method of Instruction, Faculty & Disclosure Declarations, Off-label Usage Disclosure, and Disclaimer, as well as policy statements in regard to confidentiality, conflict of interest and limitations on data.  To obtain a certificate of completion please go to the website to complete the post test and evaluation. This activity is supported by educational grants from Bristol-Myers Squibb Company, Wyeth Pharmaceuticals and an educational donation from Amgen.

We hope you enjoy this activity.

OncoEd: What is the news coming out of San Antonio this year regarding metastatic breast cancer and targeted therapy?

Dr. Schwartzberg: There continues to be tremendous interest in the use of targeted therapies for metastatic breast cancer. This year at San Antonio, most of the studies that were performed in the metastatic setting are exploratory. There were not any large Phase II or III studies using targeted therapy outside of the HER2-positive area.

The one that we are, of course, very excited about is the use of bevacizumab in the setting of metastatic breast cancer. We have the results of E2100, the study that has been analyzed several times and presented at ASCO and San Antonio, with the results showing a near doubling of the progression free survival (PFS) for patients who received weekly paclitaxel  and bevacizumab compared to patients who received weekly paclitaxel alone in the first-line setting of metastatic breast cancer.[[1]]( "_ednref1") In an attempt to build on those reports, several other approaches have been taken. We are waiting for other Phase III data, but in the interim there were some other studies.

A study [reported] by Dr. Hurvitz, [was] a Phase II trial of docetaxel with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer, done by the UCLA group.[[2]]( "_ednref2") It was a single arm study, and they found an overall response rate of 49% in a group of 67 patients that were eligible for analysis. That is an extremely high rate of response compared to 30% in the E2100 study that I mentioned . It suggests that this is going to be a good treatment as well. The median time to progression was 9.3 months which compares similarly, although a little bit less than patients in the E2100 trial.

The toxicity for the addition of bevacizumab was modest. The most common toxicity of grade 3 or 4 level was hematologic and included leucopenia and neutropenia; as well, a significant number of patients had fatigue-which are the typical side effects of docetaxel by itself. So in summary, this is a promising regimen and we await Phase III data with docetaxel and bevacizumab.

Bevacizumab was also looked at in the neoadjuvant therapy, which is a good surrogate for response. There seemed to be good preliminary results in combining bevacizumab with capecitabine and docetaxel[[3]]( "_ednref3")-with a pathologic complete response rate of 22 (not necessarily higher than one would expect without bevacizumab but these are small Phase II studies).

In another study of epirubicin, cisplatin, 5-FU, bevacizumab (which was done in Italy), a pathologic complete response rate of approximately 30% was seen in a small group of patients, which also looked like a promising regimen.[[4]]( "_ednref4")

Perhaps the most important lesson from this is that bevacizumab can be combined with other active chemotherapy programs including monotherapy like docetaxel or with combination chemotherapy like anthracycline-containing regimens or capecitabine and taxane regimens without an undue amount of toxicity.

OncoEd: Can you comment on data from San Antonio utilizing novel targeted strategies?

Dr. Schwartzberg: There are a number of new drugs that are being investigated for targeted therapy in the same theme of anti-angiogenic agents. Bevacizumab is the one that is approved as an intravenous antibody against vascular endotheliol growth factor (VEGF) but there are other factors that have been approved in other diseases. And there is a tremendous interest in small molecule anti-angiogenic factors that are tyrosine kinase inhibitors of VEGF. One of those that is approved in renal cancer is sunitinib and that was studied with paclitaxel in a Phase I study.[[5]]( "_ednref5") Its a small Phase I, but it was generally well tolerated, and the adverse events were typical adverse events that were seen with either of those drugs- typically things like fatigue, diarrhea, change in tastes (most commonly with that combination) as well as some neuropathy and skin changes. The pharmacokinetics looked good with no pharmacokinetic interaction between paclitaxel and sunitinib. There is a Phase III trial underway with sunitinib and paclitaxel versus bevacizumab and paclitaxel. This was welcome information to support the use of that trial clinically.

There was also a study of vandetanib with docetaxel as a second-line treatment for advanced breast cancer.[[6]]( "_ednref6") This was a double-blind placebo controlled, randomized Phase II study, so a bit larger trial with more clinical power to detect the actual benefit of adding this drug. Vandetanib is an oral VEGF receptor inhibitor that also has anti-EGF receptor inhibition properties. This is an interesting agent that is also being explored in other diseases. Unfortunately, in this study it did not meet its primary objective of demonstrating an efficacy benefit for vandetanib plus docetaxel versus docetaxel plus placebo. There may have been some study-specific procedures that led to that, but nonetheless there did not seem to be a big advantage to adding this drug to docetaxel in this setting as a second-line therapy. That is a bit reminiscent of using bevacizumab with capecitabine in the advanced breast cancer setting, where there was not much benefit either. This may be drug-specific, that it may not add much in breast cancer or it may add to the idea that the use of anti-angiogenic therapy in breast cancer may be best reserved for the first-line setting; but we just dont know the answer to that yet.

Another drug, AZD2171, a tyrosine kinase small molecule inhibitor of VEGF receptors 1, 2 and 3, was the subject of a Phase II trial, single-agent, monotherapy by Dr. Mayer.[[7]]( "_ednref7")  The drug as a single agent was tolerable with typical toxicities of this class of agents being hypertension and fatigue and sometimes GI toxicity. They saw a 10% response rate and that 10% response rate is a theme seen in multiple trials now of not only bevacizumab as a single agents in metastatic breast cancer but also with sunitinib as a single agent and sorafenib, another VEGF inhibitor thats in the process of being tested in randomized Phase II studies in breast cancer, which were not reported at this years San Antonio. A 10% response rate looks to be a very similar base response rate for this class of agents. What that suggests is that anti-angiogenic agents in breast cancer, as their use has been found in other common solid tumors like lung cancer and colon cancer, are best used in combination therapy with active chemotherapy. It also points out the fact that we still dont really understand how anti-angiogenic factors work because they may work to help chemotherapy delivery or they may work by blocking the formation of new blood vessels to tumors or several other mechanisms. That remains to be elucidated.

One other small molecule tyrosine kinase inhibitor of VEGF that Id like to mention as targeted therapy is AMG706. AMG706 targets VEGF receptor 1, 2, and 3 and also platelet-derived growth factor. This was tested with paclitaxel and docetaxel in metastatic breast cancer (MBC) and looked at from a safety and pharmacokinetic perspective.7 The MTD of AMG 706, also called motesanib [diphosphate], had not yet been reached in this study, and there was no interaction with motesanib and paclitaxel or docetaxel. There were preliminary objective responses seen in a variety of doses of motesanib with both taxanes. A large randomized Phase II study with motesanib and paclitaxel is ongoing now.

OncoEd: What was the news regarding the optimal management of HER2-positive metastatic breast cancer?

Dr. Schwartzberg: Im not sure that San Antonio changed what we were going to do about the optimal management of HER2-positive metastatic breast cancer. Again, in this particular setting there were no new large Phase III randomized trials or actually even many prospective trials that would change our standard practice. Of course weve had trastuzumab, the anti-HER2 antibody, for 10 years now in the clinic since the pivotal trial was done. Clearly the use of anti-HER2 therapy has become paramount in any patient that has HER- positive disease in the metastatic setting. One of the most important themes from San Antonio, which was repeated again and again in a variety of settings, is that the biology of breast cancer is what should inform our decision making, be that in the initial choice of therapies in the adjuvant setting and certainly in the metastatic setting as well. What that means is that trastuzumab remains a central therapeutic for anti-HER2 therapy. For patients who have not received prior anti-HER2 therapy either in the adjuvant setting or those who present with de novo Stage IV disease or locally advanced HER- positive disease, trastuzumab-containing combinations remain the standard of care.

With that as a background, Ill discuss the studies from San Antonio on HER2-positive MBC. Trastuzumab can be combined with new agents. One example of that was a study that looked at a third generation vinca alkaloid, vinflunine, in combination with trastuzumab in the treatment of HER2-positive MBC.[[8]]( "_ednref8") This assessed two different treatment schedules and doses of vinflunine. The higher dose given every 3 weeks with trastuzumab was well tolerated and had extremely good efficacy with about two-thirds to 70% of patients showing a response, which is quite high and is consistent and as good as any other Phase II study. In general, Phase II studies do show higher response rates but that is very encouraging for this new drug-[results] point out the fact that trastuzumab combined with virtually any drug that has activity in the metastatic setting seems to benefit.

Most of the other posters tried to use databases to evaluate some of the questions that weve not fully answered with trastuzumab. First of all, is there benefit in using trastuzumab beyond progression of first-line therapy of trastuzumab and chemotherapy? We have never had a randomized trial that has answered that to satisfaction.

In a retrospective analysis of consecutive patients who progressed on trastuzumab-containing regimens from Italy, some of them received further trastuzumab and chemotherapy and some received further chemo.[[9]]( "_ednref9") There was no difference in TTP. This was not a randomized trial and there may have been biases associated with a clinicians decision to stop trastuzumab or continue it.

There is also a question about whether trastuzumab has any impact on patients who develop CNS metastases. In a study from Korea, a patient who had not been previously exposed to trastuzumab who developed brain mets seemed to have prolonged survival compared to those who never got trastuzumab, but again this was a retrospective analysis and is merely hypothesis generating, although interesting.[[10]]( "_ednref10")

In contrast to the study that suggested there was no benefit to using trastuzumab beyond first-line progression, a retrospective analysis of routine clinical usage of trastuzumab in Germany over a 5-year period suggested the opposite, that first of all trastuzumab was commonly used beyond disease progression in routine clinical practice and there appeared to be a significant increase in overall survival in patients who did receive trastuzumab after disease progression.[[11]]( "_ednref11") The fact that we are seeing conflicting results reflects again the potential known and unknown biases in the way that the drugs were used and the problem with retrospective analyses. Therefore we really cant answer the question without a prospective trial or a comparison to other anti-HER2 therapy.

There was a prospective trial of first-line trastuzumab, with epirubicin and cyclophosphamide, in HER2-positive breast cancer from Germany, which is somewhat different from the approach in the United States where typically anthracyclines are not given concurrently with trastuzumab because of the potential risk of enhanced cardio-toxicity when two cardio-toxic drugs are used together.[[12]]( "_ednref12") The standard of care in the United States is typically to not deliver those drugs simultaneously. However, in Germany they did that with the substitution of epirubicin, which is known to have less cardio-toxicity, for doxorubicin.

In fact they were able to deliver the drug successfully without a significant problem with cardiac dysfunction as measured by left ventricular ejection fraction or clinical heart failure. There were no cardiac-related deaths; and there were four patients out of 60  who had some change in their heart function with higher doses of epirubicin; and only one out of 60 on a lower dose of epirubicin who had any symptoms or changes associated with the regimen. The time to progressions looked good and similar to what one would see with other combination chemotherapy plus trastuzumab in the first-line setting. That gives us a little bit of comfort that [trastuzumab/epirubicin/cyclophosphamide] could be a regimen that could be used.

For other HER2-positive therapy, the exciting news has been the clinical introduction of lapatinib, which is an oral small molecule tyrosine kinase inhibitor of both EGFR or HER1 as well as HER2, so it is a dual HER-family inhibitor. Lapatinib has been tested in combination with capecitabine compared to capecitabine alone in HER2-positive patients; that led to the FDA approval of that drug.

There was some further analysis from a trial that was presented at San Antonio of lapatinib and capecitabine for the treatment of brain metastases.[[13]]( "_ednref13") This has previously been reported at ASCO but these were updated results. One of thirteen patients (20%) who received lapatinib and capecitabine, having failed lapatinib for brain metastases as a monotherapy, achieved a 50% reduction in the volume of their brain metastases. Over a third of patients had a 20% reduction. Thats very interesting because it raises the idea that there may be CNS-related synergy of HER2-directed therapy and chemotherapy. We cant exclude the possibility that capecitabine alone might have caused these results since all of these patients had failed lapatinib, but at least my clinical experience is that single-agent chemotherapy is relatively ineffective against CNS metastases. So this is an exciting lead that needs to be further pursued.

The last thing on this topic is ARRY543, which is a dual inhibitor of EGFR and HER2, an oral agent with good tolerance in an escalating dose for patients in a Phase I study.[[14]]( "_ednref14")

OncoEd: Chemotherapy is still a mainstay of breast cancer treatment. What current issues are important related to using chemotherapy in the metastatic setting?

Dr. Schwartzberg: I think the most important issue in using chemotherapy in the metastatic setting is developing a plan for patients that go beyond [just considering] a line of therapy. MBC can now be subsetted into a variety of different groups. We talked about the HER2-positive groups and its interesting to reflect that the group that used to have the worst prognosis in MBC, the HER2-positive group, has now arguably been transformed into the group with the best prognosis, in terms of median survival, with the use of anti-HER2 therapy. The other large groups of patients who receive chemotherapy are those that fail hormonal therapy or hormone-receptor positive tumors that eventually run out of endocrine options and receive chemotherapy. And then the group of patients that are triple-negative, that is ER-negative, PR-negative, and HER2-negative, also considered to have the basal phenotype by genotyping. There is a lot of overlap between the phenotypic triple-negative and the genotypic basal. [Researchers] are trying to develop chemotherapy that would work well in each of those groups. We are not yet at the point of being able to subset patients who derive a specific benefit from particular chemotherapy in one of those subgroups.

Currently, the approaches to the non-HER2 positive groups are still to look at all-comers, and we typically consider either giving monotherapy to MBC patients with the idea that there would be less toxicity and we can use sequential single agents, or in some cases we use combination therapy. I lean towards combination therapy when a patient has extensive visceral disease burden or is symptomatic from their metastatic disease or has rapid progression of disease where I feel that getting a better response faster is the most important aspect of the treatment.

Many studies are looking at either combination therapies or comparing combination therapies. And as an example of that was the German breast cancer study group that looked at combination capecitabine plus paclitaxel versus epirubicin plus paclitaxel for high-risk MBC.[[15]]( "_ednref15") They found that capecitabine plus paclitaxel was an active regimen, although perhaps slightly less active than epirubicin and paclitaxel. It had a favorable toxicity profile and they believed that it was a good platform for adding bevacizumab in the future.

Other combinations have been tested, for example: weekly irinotecan and docetaxel in a North Central Cancer Treatment Groups study .[[16]]( "_ednref16") This particular study that looked at irinotecan and docetaxel did not show any particular benefit to that combination with PFS of about 6 months, which would not be substantially better than other combinations.

There continues to be work looking at combination therapy. I think increasingly we will continue to see new drugs being developed which are cytotoxic agents, and we will also see the increasing use of both monotherapy and combination chemotherapy combined with biological therapy.

OncoEd: A new agent ixabepilone was recently approved by the FDA in combination with capecitabine in MBC patients who have failed an anthracycline and a taxane. Can you comment on the data presented at San Antonio?

Dr. Schwartzberg: Ixabepilone is a first in class agent. It is a substitution of a natural class of drugs called epitholone-Bs. These are microtubule toxins, which bind to different parts of the microtubule, [assembly apparatus compared to] for example vincas or taxanes. Ixabepilone was recently approved, based on a number of studies in patients that were both anthracycline- and taxane-resistant, a very difficult group of patients to treat with MBC, since typically anthracyclines and taxanes would be used in the first- and second- line of previously untreated patients. Ixabepilone showed substantial activity in that setting, either as a single agent or combined with capecitabine. One of the pivotal trials that led to the approval of ixabepilone was a randomized trial of capecitabine alone versus capecitabine and ixabepilone.

At San Antonio there was a further analysis of this trial, which looked at the subgroups that Ive mentioned before.[[17]]( "_ednref17") The idea was: could we define a chemotherapy regimen that has particular activity against one of the other subgroups and start using chemotherapy based on biology rather than simply metastatic breast cancer outside the HER2 setting? In this analysis, done by Dr. Rugo, the patients who had triple-negative breast cancer had a 3-fold higher response rate to ixabepilone and capecitabine of 27% compared to those with capecitabine alone only at a 9% response rate. That should be considered against the response rate in all patients in that large Phase III trial, which was 35% for ixabepilone and capecitabine versus 14% for capecitabine alone. What this shows is at least a hint that ixabepilone may have preferential activity in the triple-negative subset and that capecitabine as a single agent has very modest activity against this group of patients, which is an observation that we have seen with many other single agents. This is a particularly hard group of patients to treat. This will lead to further testing of ixabepilone in this subgroup.

In addition, a Phase II trial of trastuzumuab, weekly ixabepilone and carboplatin in patients with HER- positive disease was presented.[[18]]( "_ednref18") This was an ECOG trial. It built on previous data from the ECOG group that demonstrated that combination of carboplatin and paciltaxel with trastuzumab was an extremely active regimen in HER2-positive patients. They treated 59 patients and had an overall response rate of 44%, which was similar to that seen in previous taxane-based regimens. Their primary objective was to show superiority for this regimen over paciltaxel/carboplatin/trastuzumab, which they did not do.

This study taken with the other trial that I just mentioned suggests that ixabepilone does not offer advantage in the HER2-positive group over other taxanes but may in the triple-negative group.

OncoEd: What do you consider promising agents in Phase II trials for MBC presented at San Antonio?

Dr. Schwartzberg: I already mentioned vinflunine, which has been previously tested as a single agent and is now being tested with trastuzumab with very high responses. One of the other Phase II agents that was tested was bosutinib.[[19]]( "_ednref19") This drug, also called SKI606, is a dual Src-Abl kinase inhibitor. Src is a protein that is a non-receptor tyrosine kinase that has many activities within cells and is increasingly recognized as an important component of MBC, particularly with regard to increasing breast cancer cells ability to migrate and invade and possibly have metastatic potential. Drugs of this class are being investigated now and are of high interest.

This is the first Phase II study that I am aware of with a drug of this class. This was an open-label single-agent study of this oral therapy. There were 73 patients treated. The response rate was 6% as a single agent, which is modest but it wouldnt necessarily be considered that a drug of this class would be a good agent to actually cause shrinkage of tumor. But because of its putative mechanism of action inhibiting Src, it may be better at preventing progression of disease. In fact, if one looked at PFS, it was 15 weeks in this heavily pretreated group of patients that had a median of 4 prior regimens of chemotherapy. So a 4-month time until they progressed would seem to be very interesting. There were 4 partial responses as I said to a drug with a novel target. Thats very interesting and we will see other studies. In fact, I am involved in a trial with chemotherapy and another Src-Abl inhibitor myself.

Another drug of interest was HKI-272.[[20]]( "_ednref20") HKI-272 is in irreversible pan erbB2 tyrosine kinase inhibitor. Tthis targets all 4 members of the erbB or HER pathway, 2 different names for the same receptor family. As a pan inhibitor this has great interest. This is again a smallmolecule TKI that is delivered orally. There were 102 patients that received the drug. The PR rate was 10% and there were a number of patients who had stable disease. A small group of patients who had not received any prior anti-HER2 therapy had a very prolonged PFS of 33 weeks. For patients who had previously received trastuzumab for HER2-positive disease, they had a PFS of 16 weeks but had a very respectable response rate of 30% to the same single-agent treatment. I should mention that all patients on this study had HER2-positive disease, proven by gene amplification by FISH testing. This is a further exploration of that pathway, which is going to be an important one going forward.

OncoEd: What do you consider the most urgent priorities for future clinical trials in the metastatic setting?

Dr. Schwartzberg: It goes back to what I [previously] said: I think the theme of San Antonio is one size does not fit all. We have an urgent need to develop therapies that target the two other large subgroups of patients, that is ER-positive patients that progress after hormonal therapy and then the triple-negative groups, which is already starting to be explored with both biological therapies and other novel chemotherapies in combinations. There have been surprisingly few analyses of a differential response by chemotherapy for patients who have a phenotype of ER-positive, despite having used chemotherapy in this group of patients for many decades now. So thats an important priority. I think the most urgent priority is to continue the exploration of the anti-angiogenic pathway in breast cancer, which seems very [clinically] profitable, as well as other novel targets and subgroups.

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[[1]]( "_edn1") Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of Taxol versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100).Breast Cancer Res Treat. 2005;94(Suppl 1):S6 (Abstract #3).

[[2]]( "_edn2") Hurvitz SA, Kabbinavar FF, Allen HJ, et al. A phase II trial of docetaxel with bevacizumab as first line therapy for Her2/neu negative metastatic breast carcinoma. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4062.

[[3]]( "_edn3") Greil R, Moik M, Reitsamer R, et al. Capecitabine + docetaxel + bevacizumab as neoadjuvant therapy for invasive breast cancer: results of a phase II pilot study. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4064.

[[4]]( "_edn4") Ferrari B, Scarano E, Pietri E, Dellapasqua S, Colleoni M. Bevacizumab combined with chemo-endocrine preoperative therapy in locally advanced operable breast cancers. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4063.

[[5]]( "_edn5") Kozloff MF, Chuang E, Roy J, et al. A phase I study of sunitinib plus paclitaxel for first-line treatment of advanced breast cancer: preliminary results. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6078.

[[6]]( "_edn6") Boer K, Lang I, Llombart-Cussac A, et al. Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo controlled, randomized phase II study. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6081.

[[7]]( "_edn7") Mayer EL, Hamel S, Savoie J, et al. AZD2171 for refractory breast cancer: a phase 2 trial. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6080.

[[8]]( "_edn8") Paridaens R, Wildiers H, Dalenc F, et al. Vinflunine in combination with trastuzumab: an active combination in the treatment of HER2 positive metastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 1082.

[[9]]( "_edn9") Montemurro F, Viale G, Donadio M, et al. Retrospective evaluation of clinical outcomes in HER2-positive advanced breast cancer patients progressing on trastuzumab-based therapy in the pre-lapatinib era. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4057.

[[10]]( "_edn10") Nam BH, Kim SY, Han HS, Lee KS, Ro J. Survival gain by trastuzumab therapy after the onset of intracranial metastasis in metastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4061.

[[11]]( "_edn11") Jackisch C, Eustermann H, Schoenegg W, et al. Clinical use of trastuzumab (Herceptin) in metastatic breast cancer (MBC) in Germany from 2001 to 2006. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4059.

[[12]]( "_edn12") Untch M, Tjulandin S, Jonat W, et al. Evaluation of first-line trastuzumab in combination with epirubicin/cyclophosphamide for patients with HER2-positive metastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4058.

[[13]]( "_edn13") Lin NU, Paul D, Dieras V, et al. Lapatinib and capecitabine for the treatment of brain metastases in patients with HER2+ breast cancer  an updated analysis from EGF105084. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6076.

[[14]]( "_edn14") Gelmon K, Kane K, Kollmannsberger C, et al. A phase 1 study of ARRY-543, a potent, selective, reversible inhibitor of ErbB receptors. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6071.

[[15]]( "_edn15") Lück H-J, du Bois A, Schrader I, et al. Final results of the AGO breast cancer study group MAMMA-3 trial: first-line capecitabine + paclitaxel vs epirubicin + paclitaxel for high-risk metastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 1076.

[[16]]( "_edn16") Tan WW, Hillman D, Salim M, et al. N0332 phase II trial of weekly irinotecan and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group trial. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 1087.

[[17]]( "_edn17") Rugo HS, Thomas ES, Lee RK, Fein LE, Peck R, Verrill M. Combination therapy with the novel epothilone B analog, ixabepilone, plus capecitabine has efficacy in ER/PR/HER2-negative breast cancer resistant to anthracyclines and taxanes. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6069.

[[18]]( "_edn18") Moulder S, Wang M, Gradishar W, et al. A phase II trial of trastuzumab, weekly ixabepilone (BMS-247550) and carboplatin (TIC) in patients with HER2/neu-positive (HER2+) metastatic breast cancer (MBC): a trial coordinated by the Eastern Cooperative Oncology Group (E2103). Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6070.

[[19]]( "_edn19") Campone M, Bondarenko I, Brincat S, et al. Preliminary results of a phase 2 study of bosutinib (SKI-606), a dual Src/Abl kinase inhibitor, in patients with advanced breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6062.

[[20]]( "_edn20") Burstein H, Awada A, Badwe R, et al. HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: preliminary phase 2 results in patients with advanced breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6061.