Breast Cancer Update Issue 6, 2007

DR WILLIAM J GRADISHAR: EFECT was an effort to address the issue of what to do for patients who receive nonsteroidal aromatase inhibitors as treatment in the adjuvant or metastatic setting and then develop progressive disease. We want to know if an optimal sequence exists for endocrine therapy.

Other pilot studies suggested that you could switch from a nonsteroidal aromatase inhibitor to fulvestrant, a selective estrogen receptor regulator, and obtain a clinical response. EFECT attempted to rigorously address the issues of which agent to employ in this setting and whether using a loading dose of fulvestrant might lead to a more rapid achievement of steady-state drug levels.

Regarding efficacy, nearly every endpoint was superimposable. Whether you compare response rate, time to disease progression or tolerability and adverse events, patients who received either fulvestrant or exemestane had identical outcomes in all of those categories.

The conclusion is that one could legitimately approach a patient who has experienced progression on a nonsteroidal aromatase inhibitor with either one of these agents. It’s not absolutely clear whether a superior sequence exists, however.

Breast Cancer Update Issue 3, 2008

PROFESSOR JOHN F R ROBERTSON: I believe it is reasonable to consider ovarian suppression in combination with fulvestrant for a premenopausal patient with metastatic breast cancer. Gunter Steger’s work shows response rates in the range that one would expect from an effective endocrine agent. I believe that if you’ve used other, perhaps more established, options, such as goserelin and tamoxifen or goserelin and anastrozole, and you’re searching for an alternative, then that’s reasonable for a patient with hormone-sensitive disease.

Click on the image to enlarge

Breast Cancer Update Think Tank Issue 1, 2008

DR CARLSON: Currently, the use of bevacizumab and paclitaxel in the first-line treatment of metastatic disease is included in the NCCN guidelines as an option. The NCCN panel does not require FDA approval of an agent and a specific indication to incorporate it into the guidelines, nor does FDA approval mean that it is incorporated into the guidelines. The NCCN Breast Cancer Committee to date does not focus specifically on progression-free survival, overall survival or toxicity. It’s more a gestalt or a balance between the experts on the panel in terms of weighing the different advantages.

Breast Cancer Update SABCS Satellite Symposium 2008

DR HUDIS: ECOG-E2100 is the informative study for the question at hand. The trial demonstrated that the addition of bevacizumab to a three-out-of-four-week paclitaxel schedule was associated with a near doubling of progression-free survival, a remarkable increase in response rate and a nonstatistically significant trend in favor of an improvement in overall survival.

We have nonrandomized trial data with several of the first-line agents and several of the taxanes. Albumin-bound paclitaxel was studied in a retrospective fashion along with the bevacizumab, suggesting a reasonable response rate of approximately 50 percent.

DR G THOMAS BUDD: For a patient with visceral disease who has not received adjuvant chemotherapy, I would think of a taxane, and I would use bevacizumab. I usually use paclitaxel. I think nab paclitaxel is a perfect alternative — we have safety data with it.

DR GEORGE W SLEDGE JR: A taxane-based regimen with bevacizumab would certainly be my front choice, assuming the insurance paid for it.

Breast Cancer Update Issue 7, 2007

PROFESSOR IAN E SMITH: In the United Kingdom, the bevacizumab data haven’t influenced the use of capecitabine. I believe capecitabine is a useful drug for metastatic breast cancer for all the obvious reasons.

Women who’ve already experienced relapse after standard adjuvant therapy are demoralized, and the problems of returning to all the standard chemotherapy options are obvious. Capecitabine is, by and large, well tolerated.

I believe dose is important. To be technical, the standard dose is 2,500 mg/m² in divided doses (ie, 1,250 mg/m² twice a day). That dose can cause a lot of toxicity. MD Anderson published data a few years ago showing outcomes if the dose was reduced a little, to 1,000 mg/m² twice daily.

This wasn’t a randomized trial — they simply reviewed the data — but the outcome was as good, and the toxicity with capecitabine is dose dependent. We now start patients with a dose of 1,000 mg/m² twice daily for 14 days, and most people tolerate that well.

We published a study describing a series of patients who received that dose of capecitabine, and I believe the efficacy was similar to what we would see at a higher dose. In adjuvant therapy with curative intent, the dose is crucial. You don’t want to shortchange patients. Once you’re dealing with metastatic disease, it’s a balance.

Obviously, patients want to stay alive, but patients can stay alive using a little dose reduction — it is difficult for me to imagine that a small dose reduction will make a big difference in terms of survival. However, you can see that the lower dose makes a big difference in terms of quality of life.

Click on the image to enlarge

Breast Cancer Update Issue 6, 2007

DR SLEDGE: We launched a multicenter study, XCaliBr, with patients who were similar to the patients from ECOG-E2100. They had HER2-negative breast cancer and were receiving their first chemotherapy for metastatic disease. These patients were treated in a Phase II, single-arm setting, and all received the combination of bevacizumab and capecitabine until progression. At the time of progression, they crossed over and continued to receive bevacizumab with either a taxane — paclitaxel — or vinorelbine.

We have data from the first portion of that trial, and the median progression-free survival for patients receiving bevacizumab and capecitabine was 5.7 months, which is a disappointing result compared to the 11 months we saw with the combination of paclitaxel/bevacizumab in ECOG-E2100.

Click on the image to enlarge

Breast Cancer Update SABCS Satellite Symposium 2008

DR JOSEPH A SPARANO: For a patient with visceral disease who has received an adjuvant anthracycline, paclitaxel/bevacizumab would be an appropriate choice. It would be my choice. If bevacizumab were not available, then this is the type of patient for whom I would recommend a couplet that includes a taxane.

Breast Cancer Update Issue 2, 2008

DR O’SHAUGHNESSY: When a patient who has previously received an anthracycline and a taxane presents with metastatic visceral disease and needs a response to first-line therapy, I turn to a bevacizumab regimen. I want to use it up front, when the safety is the best, and I want to obtain prolonged progression-free survival. I don’t have a strong preference between paclitaxel and nab paclitaxel. All things equal, I’d probably use nab paclitaxel with the idea of trying to provide a longer run on the taxane before causing toxicity.

Breast Cancer Update Think Tank Live 2007

DR ERIC P WINER: Typically, for a patient with triple-negative breast cancer who develops a relapse soon after receiving adjuvant chemotherapy, 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 disease-free interval of at least 12 months, and they derived a significant benefit from paclitaxel and bevacizumab.

DR SLEDGE: Approximately one in five patients entering the trial had received an adjuvant taxane for 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.

I believe this is a case in which you sit down and discuss the factors with the patient. An 11-month progression-free survival is good in the metastatic setting. I do not see a lot of evidence indicating that we should be using bevacizumab further along. We have no evidence for benefit with this agent for anything other than front-line metastatic breast cancer. If I were going to use bevacizumab, I would use it up front.

Breast Cancer Update SABCS Satellite Symposium 2008

DR HUDIS: Until the ECOG-E2100 data were reported, I was consistently choosing capecitabine as first-line chemotherapy for patients who have received both an anthracycline and a taxane as adjuvant therapy. In ECOG-E2100, the delta gain and the point estimates with bevacizumab were similar for the patients who were pretreated and those who were not. If patients have completed more than a six-month or a one-year interval from their adjuvant taxane, I’m comfortable — if they’re tolerant of the toxicity — resuming it and using bevacizumab.

Breast Cancer Update Think Tank Issue 1, 2008

DR HUDIS: In an effort to address the question of which chemotherapy to combine with bevacizumab in the metastatic setting, the CALGB has proposed a trial evaluating first-line therapy with bevacizumab in combination with paclitaxel, nab palcitaxel or ixabepilone. Hope Rugo is a principal investigator of this prospective, randomized, Phase III trial along with Alvaro Moreno from the NCCTG. They proposed a Phase II randomized trial of ixabepilone versus paclitaxel in combination with bevacizumab. We proposed a Phase III trial of weekly paclitaxel versus nab paclitaxel. CTEP asked us to collaborate and join these two studies.

Weekly paclitaxel, for three weeks out of four, with bevacizumab is the control regimen. The two experimental arms administer weekly ixabepilone or weekly nab paclitaxel, both with bevacizumab. Significant correlative science studies are also built into the study. The cooperative groups wrote the study with progression-free survival as an endpoint. However, FDA-related discussions are ongoing as to whether or not this study will be adequate for drug approval and, therefore, how we should move forward.

Breast Cancer Update Issue 2, 2008

DR O’SHAUGHNESSY: The trial comparing bevacizumab in combination with ixabepilone, paclitaxel or nab paclitaxel is a great study. I believe the dose of each agent is optimized. It may be difficult to discern large differences in efficacy with those three agents combined with bevacizumab, because I believe bevacizumab will enhance the activity of all of them. The issue will be toxicity, which I believe may be similar with nab paclitaxel and weekly paclitaxel with regard to neuropathy, because the dose of nab paclitaxel is being pushed.

Interview, April 2008

DR MILLER: Investigators and clinicians have posed important questions that are not being addressed in clinical trials. One question relates to the continuation of bevacizumab in breast cancer, which we’ve thought to be important for several years. Unfortunately, it is not a trial that the NCI is inclined to support.

For three years now, we’ve heard talk about it and assurance that there is interest, and they’ve been calling it the RIBBON 3 trial. Three years later, there is no final design for the trial and it’s not moving forward. Yet some are inclined to use bevacizumab the way trastuzumab is used.

This brings us to the colon cancer trial, the BRiTE registry and using bevacizumab beyond disease progression. People tend to refer to the BRiTE registry as if it were a randomized trial. However, it is important to acknowledge the difference.

One issue with extrapolating the colon cancer data is that the patients were selected, suggesting a certain degree of bias. The registry is essentially a collection of 2,000 anecdotes. It doesn’t tell us much, except that in the absence of data this is what we have to go by. People see the differences, and the message that they take away from it is, look at this difference in overall survival with bevacizumab beyond progression. But these are not concrete data, and I still think it’s a crucial issue that needs to be addressed by a randomized trial.

Breast Cancer Update Issue 3, 2008

DR ROBERT: The opportunity to study HER2-based regimens generation after generation, or on different lines, is probably closed. However, perhaps we can develop bevacizumab in a more responsible way. I support the idea of a RIBBON 3 trial and maybe even a RIBBON 4 trial. In individualizing care, I would be tempted to continue bevacizumab for some patients, if money were not an issue. However, to date I have not done so, partly because of the reimbursement issue but also because we don’t have enough data to push me to do so.

Breast Cancer Update Think Tank Issue 2, 2007

DR HOWARD A BURRIS III: The decision whether to continue bevacizumab upon progression is difficult. I see more and more patients who have finished weekly paclitaxel and bevacizumab, and they’re being treated with maintenance bevacizumab. If they’re feeling well and their disease is gradually regrowing, I continue bevacizumab and add a second drug. For patients who clearly aren’t benefiting or are fighting the toxicity, it’s easy to think about discontinuing bevacizumab. In general, however, it’s been well tolerated.

DR HAROLD J BURSTEIN: I believe continuing bevacizumab after progression is not a great strategy. We all lapsed into this behavior with trastuzumab, which perhaps was correct or perhaps was incorrect. Considering the concerns about some of bevacizumab’s side effects, the absolute unknowns about its role and the fact that we have a negative study in the second-line setting, it’s hard to believe that a huge clinical advantage exists for continuing bevacizumab.

DR SLAMON: If we had a way to identify a patient who was responding to bevacizumab, we’d have little doubt that staying with the agent and adding another drug later would also continue to benefit the patient, as it has with trastuzumab. We don’t have hard data, but that’s what I would do clinically. These drugs are safe, and we know the toxicities. We can administer them safely, and I believe they should be used.

Breast Cancer Update Issue 3, 2008

DR GRALOW: Trastuzumab is a large monoclonal antibody that shouldn’t be able to cross the intact blood-brain barrier. However, some anecdotal case reports indicate that once you have a large metastasis that disrupts the blood-brain barrier, you can obtain tumor shrinkage with trastuzumab.

Lapatinib certainly penetrates the blood-brain barrier, and we have some anecdotal evidence suggesting that we can achieve tumor shrinkage with lapatinib alone. Nancy Lin and the group at Dana-Farber have conducted elegant studies for patients with HER2-positive brain metastases who received radiation therapy and whose disease was progressing. They added lapatinib as a single agent.

Using conventional measures, lapatinib alone has not produced much of a response. It’s making a dent, but it doesn’t meet the classic response criteria.

When patients on those studies experienced disease progression or no response on lapatinib, capecitabine was added and quite a few responses then met conventional criteria. Whether it was the combination of capecitabine/lapatinib or the capecitabine alone, I’m not sure.

I’m also tantalized by evidence in the Phase III trial of capecitabine/lapatinib versus capecitabine, which indicated a numerical trend toward fewer brain metastases with lapatinib.

Breast Cancer Update Issue 1, 2008

DR GEYER: Some studies suggest that a substantial proportion of the patients who die from HER2-positive breast cancer are probably dying in part from uncontrolled CNS disease. The hope is that lapatinib, being a small molecule, will penetrate. Some studies have evaluated lapatinib in heavily pretreated patients with brain metastases, and they did see activity, but it didn’t meet the study criteria they were hoping for — it’s a tough population.

In our trial comparing capecitabine with or without lapatinib in women with advanced breast cancer who progressed on trastuzumab, 13 patients on capecitabine alone developed symptomatic CNS disease as part of their first site of progression, whereas only four patients on the combination did so, which I believe is a notable result.

I see clinicians struggle with what to do when a patient is well systemically on trastuzumab and then develops brain metastases. Do you switch to lapatinib? Do you add lapatinib? A number of clinicians choose the combination, but do they know that when they do so, they have to use a lower dose of lapatinib to make it tolerable with trastuzumab? The question is, if we lower the dose of lapatinib, do we know if it is reaching the brain? We don’t have the answer, so I have concerns about the combination.

Breast Cancer Update Think Tank Issue 1, 2008

DR ANTONIO C WOLFF: I’m surprised that, thus far, I haven’t had any patients who have experienced a cancer relapse after receiving adjuvant trastuzumab, and we were active participants in NCCTG-N9831. Perhaps the window of relapse will be early, and it may plateau later on. Or maybe some of these patients who have not experienced a relapse never will — that would be wonderful.

The major concern is that we have no idea what prior trastuzumab will mean in this situation. I am not sure what these artificial boundaries of six, 12 or 24 months mean, but at some point you need to draw the line. I believe that if someone has an immediate relapse within the first year after trastuzumab, I would be more nervous about attempting to use a trastuzumab-containing regimen and may proceed to lapatinib. But again, we are making artificial decisions.

Breast Cancer Update Think Tank Live 2007

DR SLAMON: If a patient has received a trastuzumab regimen and has experienced a relapse quickly — within a year after receiving adjuvant trastuzumab — I consider an alternative targeting agent such as lapatinib.

If a year, 18 months or more has passed, I consider using trastuzumab with another therapeutic agent — vinorelbine or gemcitabine. A number of agents can be used while still on trastuzumab.

Breast Cancer Update Think Tank Live 2007

DR WINER: A patient who develops a recurrence while receiving or soon after receiving a combination of adjuvant trastuzumab and chemotherapy, in my mind, is 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 be my choice for patients who experience relapse during adjuvant therapy. For a patient who has a cancer relapse 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 this situation much differently than I would approach a patient who presents with de novo HER2-positive disease.

Select Publications