Breast Cancer Update 2006 (6)

DR CHARLES E GEYER JR: The exciting thing about the adjuvant trastuzumab data has been that no matter how you use it, patients derive a substantial benefit. Small differences probably occur among the different ways of using trastuzumab, which we can’t definitively address because the trials weren’t designed that way, but it’s clear that trastuzumab is the most important element of therapy for a patient with HER2-positive breast cancer.

TCH (docetaxel/carboplatin/trastuzumab) certainly has low cardiac toxicity, but TCH is not a gentle regimen for an elderly woman.

I believe the weekly carboplatin/paclitaxel/trastuzumab that we use for metastatic disease is active and well tolerated. Those are the substitutions I believe would be reasonable to consider for an elderly patient, if you felt you needed to use chemotherapy.

Can you use trastuzumab alone or with hormone therapy? I’m sure you can. You have to use your clinical judgment. Trastuzumab is active without chemotherapy; there is no question about that, but if I were going to use trastuzumab, I would like to use some kind of chemotherapy, maybe just four cycles á la the HERA trial.

Breast Cancer Update 2006 (7)

DR TRIPATHY: Theoretically, adjuvant trastuzumab monotherapy may be a reasonable approach. Remember that in the HERA study, a 50 percent reduction in recurrence was seen in all patient groups, which included all comers. But keep in mind that as a requirement of the HERA study, all patients received prior chemotherapy. We know that synergy exists between chemotherapy and trastuzumab, so we could argue that trastuzumab works best in the context of chemotherapy. Although I would guess that trastuzumab monotherapy would reduce recurrence, we don’t have any data to support that. Sometimes extrapolations require too much speculation, and I believe the leap to trastuzumab monotherapy is one of those situations.

Trastuzumab monotherapy would be good to include in a trial if we could identify an appropriate patient population. We currently have options for chemotherapy regimens that are nontoxic, like some of those used in the HERA trial. Dr Heikki Joensuu has studied vinorelbine followed by FEC, opening the door to studies of agents with pre-clinical synergy and great activity in the advanced setting. I would advocate a trial, maybe with vinorelbine and trastuzumab in one arm and trastuzumab alone in another arm.

Combining a taxane alone with trastuzumab is a little more reasonable, although again, we do not have the data. Technically, the HERA study would have allowed that, but I don’t think there were any patients who received paclitaxel alone. In talking about where one would draw the line, a taxane alone with trastuzumab, in my mind, would be reasonable.

Breast Cancer Update 2006 (7)

DR PEGRAM: If you’re going to consider an anthracycline-based adjuvant regimen followed by trastuzumab with taxanes, you need to tell patients that it carries a defined risk of cardiotoxicity. In particular, in the NSABP-B-31 adjuvant trastuzumab trial, after four cycles of AC approximately four to five percent of the patients were ineligible for adjuvant trastuzumab at all. In clinical practice, it is important to measure the ejection fraction before and after the AC to make sure that your patient would have met the eligibility for the study and you could draw on that safety database.

Moreover, during the year of adjuvant trastuzumab for the patients who received the drug, an additional approximately 15 percent of the patients had to drop out because of decreases in ejection fraction, which I find alarming. My fear is that in the community, busy practitioners will forget to obtain those ECHOs and MUGAs every three months, which was done on all of the adjuvant trastuzumab trials.

I’m fearful of what might happen for patients who have marked decreases in ejection fraction but may not be having symptoms from heart failure yet, and because they didn’t get their ECHO or MUGA they are simply continued on more trastuzumab. Clinicians need to know that if they’re going to prescribe adjuvant trastuzumab, they should do so following the same guidelines that were used in those protocols, which was an ejection fraction assessment every three months during the one year of trastuzumab.

If the ejection fraction decreased to less than institutional norms, patients had to drop out. If it dropped 15 points and was above institutional norms, they had to hold the trastuzumab, at least temporarily, and wait for recovery. If recovery was evident on a follow-up one month later, then they were allowed to attempt to reinstitute it, as long as they were not symptomatic or at lower than institutional norms. These protocol guidelines are available, and they should be strictly followed if you’re going to use anthracyclines.

Breast Cancer Update 2006 (6)

DR GEYER: For me, the precedent for cardiac monitoring of a patient receiving trastuzumab has been set by the adjuvant trials. The plan was a reasonable one: Check imaging halfway through the chemotherapy, check it at the end of chemotherapy and then check it three months later. It made sense for the trial, and I believe it makes sense for the clinic.

In NSABP-B-31 and NCCTG-N9831, we stopped the drug in a significant number of patients — about 15 percent of the patients had asymptomatic declines in LVEF. We don’t know that we would have seen a higher rate of clinical heart failure if we had continued to treat them, but it’s a reasonable assumption.

Breast Cancer Update 2006 (8)

DR BURSTEIN: The biggest question I get at tumor boards right now is how to approach patients who have small HER2-positive tumors — patients who wouldn’t have been eligible for the adjuvant trials, such as the patient with the 7-mm, ER-negative, HER2-positive tumor or the 1.2-cm, ER-positive, HER2-positive tumor.

We don’t have great data on the outcomes for these women. We have proposed, and I believe we’ll put forward, a multicenter trial evaluating trastuzumab with paclitaxel as a treatment regimen for patients at low risk. We will treat something in the order of 300-400 patients in what will essentially be a feasibility study to show that if you carefully select the patients at low risk and administer a paclitaxel/trastuzumab combination that should be well tolerated, you have a low risk of recurrence.

We would love to see a huge randomized trial for these women, but that is impractical given the resources and the generally low risk for patients with node-negative disease.

Breast Cancer Update 2006 (8)

DR RAVDIN: Currently, the Adjuvant! program doesn’t make projections for trastuzumab outcomes at 10 years because we have data with follow-up of only two to three years. In general, many of the patients with ER-positive disease will experience recurrence later. If we don’t know that part of the story, we could give wildly inaccurate estimates. Instead, the program provides a separate output for trastuzumab, projecting benefit at five years, which is reasonable to talk about.

Some patients have been followed for five years in the trastuzumab trials.

The program also provides information about some of the toxicities and uncertainties about toxicity. Version 9 of the breast cancer program is about to be released. For the first time, it includes HER2 status as one of the program parameters.

Breast Cancer Update 2006 (7)

DR PEGRAM: Fulvestrant, rather than tamoxifen or the aromatase inhibitors, makes the most sense to combine with trastuzumab because in HER2-positive breast tumor cells there is ligand-independent activation of the estrogen receptor. That is, the cross talk between HER2 signaling and the estrogen receptor can activate estrogen-dependent genes in the absence of estradiol.

The aromatase inhibitors remove the ligand for the ER, but the ER can still be turned on by HER2 signaling. So that’s a strike against aromatase inhibitors. Tamoxifen can also be more agonistic as a result of this cross talk mechanism.

The question is, how can you tackle such a complex issue? It would be ideal to eliminate the estrogen receptor, and that’s exactly what fulvestrant does.

Therefore, it is appealing from a theoretical point of view to incorporate HER2-directed therapy with fulvestrant, and we have a randomized Phase II trial under way in the metastatic setting comparing fulvestrant alone to trastuzumab alone to the combination. It’s accruing slowly, unfortunately, and may have to be pared down to get some point estimate on the activity of the combination in the future.

I have a number of patients on fulvestrant and trastuzumab who are doing well, although they were started on the treatment off protocol because our protocol wasn’t open when they started.

I’ve had some nice anecdotal responders on that combination. Remember that many of these patients have already received adjuvant aromatase inhibitors anyway. So fulvestrant is a reasonable consideration when they relapse.

Breast Cancer Update 2006 (7)

DR TRIPATHY: The patient with HER2-positive disease who was treated six months or a couple of years ago poses a dilemma. You have to decide one way or the other — if the patient comes to you, then you can’t just throw up your arms and say you don’t know. My approach is to individualize therapy.

We know that in both the HERA study and the North American studies, the hazard rate in the entire population was still pretty high at two and three years — around 10 percent per year. Now, the question is, does the risk reduction still apply two years out? That we don’t know.

I can make an analogy with hormonal therapy. I was surprised when the data came out for patients who had been on tamoxifen for five years and were then randomly assigned to placebo versus letrozole. Even when initiating hormonal therapy after five years, approximately a 40 percent reduction was still evident, which is about what we expect of hormonal therapy anyway. So at least in the case of hormonal therapy, it looks as though the odds reduction is preserved whether treatment is given up front or much later.

Extending that to trastuzumab, patients at average risk would still have an annual reduction in hazard ratio of about five percent per year. So that would be 10 percent over two years and maybe even more as time goes on. We have to realize that even two or three years out, an odds reduction is likely. Again, this is where you need to tailor treatment. For a patient with node-negative disease who is a borderline candidate, I would use trastuzumab up front or maybe six months out. For patients with two or three nodes, I believe it’s appropriate to consider trastuzumab even two years out. I know that’s a stretch, but at least it is based on data on annual hazards and some extrapolations of the activities of other drugs.

I believe it’s reasonable even when the patient was treated more than two years ago. We don’t have hazard rates that far out. Right now, we have them as far as three years on the longest-running NSABP study. Keep in mind that every year we will have more data on the annual hazards. Currently I would say two, two and a half years is my limit. But a year from now, when we will have more data, I believe we can feel more comfortable. So it’s a moving target, and we have to stay tuned.

Breast Cancer Update 2006 (8)

DR BURSTEIN: With the tremendous outpouring of the major adjuvant trastuzumab trials in 2005, a lot of retrospective clean-up work has begun. People want to see if they can figure out which tumors benefited most markedly from trastuzumab. Is there a marker — whether it’s cMYC or TOPO II — or do we have something else that will predict which patients do or don’t need trastuzumab? Which patients who receive trastuzumab have such a fabulous prognosis that they don’t need anything else?

In terms of treatment, the next big trial will be from the Breast International Group (BIG). This will be a four-arm randomized trial of trastuzumab (BIG 2-06) for patients who have HER2-positive breast cancer and have received chemotherapy. Patients will receive trastuzumab versus lapatinib versus a combination of the two versus a sequential treatment program of trastuzumab followed by lapatinib. Some patients will receive only lapatinib.

Another controversy is that this study follows the HERA treatment program, in which patients would, for the most part, receive chemotherapy first and then receive the biological therapy with the option of receiving the biological therapy concurrently with taxane therapy. I have been impressed that the best results seen with trastuzumab in the adjuvant setting and with trastuzumab and lapatinib in the metastatic setting occur when you pair these products with chemotherapy. By not insisting on administering these drugs with chemotherapy, you probably do not optimize the beneficial effects of these drugs, and that is a substantial criticism of the study.

Additionally, we have an awful lot of good-quality data on trastuzumab but not every patient will receive trastuzumab, and that will affect accrual in some quarters. A lot of excitement has arisen about lapatinib, but I believe that is a potential weakness of the study design. You have to bring new agents forward and you need corporate sponsorship for trials, so hard choices have to be made, but I believe that this will affect some patients’ and doctors’ willingness to contribute to that study.

Breast Cancer Update 2006 (6)

DR HENDERSON: TOPO II makes sense scientifically. We began talking about it more than a decade ago. It’s particularly interesting because TOPO II is on the same chromosome as HER2, and in the early papers we thought there was a correlation between the impact of doxorubicin and HER2.

I don’t believe that has really held up. Certainly, when Dan Hayes presented the data from CALGB-9344 at ASCO 2006 we didn’t see a correlation between HER2 expression and doxorubicin dose. I believe anthracyclines are so powerful and so valuable in the treatment of breast cancer that I would be hesitant to leave out doxorubicin until we had compelling data that a particular group of patients received no benefit from it.

It’s similar to the way we view estrogen receptor status and chemotherapy. We know that patients with ER-positive disease derive less benefit from chemotherapy than those with ER-negative breast cancer, but it’s not an all-or-none phenomenon.

I believe the same principle applies here. When will you be comfortable enough to leave out a powerful drug? As good as the taxanes are — and I am enthusiastic about them — I don’t believe they are any better than the anthracyclines in the treatment of breast cancer.

Breast Cancer Update 2006 (6)

DR LIPPMAN: The data on TOPO II that were presented at the San Antonio Breast Cancer Symposium were very exciting, and I hope they are substantiated. It makes biological sense — TOPO II is a target for doxorubicin. That would potentially explain which subsets of patients gained particular advantage from the doxorubicin combinations compared to the platinum combinations.

I’m not ready to draw the conclusion that Professor Slamon seemed to want to draw, which is that in those patients who did not overexpress TOPO II, the use of a nondoxorubicin-containing combination was as efficacious.

That may be true, but I’m not there yet. I believe we need more analysis. Given the additional cardiac risks of using trastuzumab with doxorubicin, particularly in older women, it would be nice to have a less cardiotoxic regimen to use. In that same regard, I found the data Soonmyung Paik presented from the NSABP on cMYC overexpression extremely exciting and, once again, biologically plausible.

cMYC is an oncogene that is generally upregulated when cells are stimulated to grow; it is part of the growth response, and it is clearly overexpressed in about 20 to 25 percent of human breast cancer cases. The question is, why is it that many patients with tumors that unquestionably overexpress HER2 do not respond to trastuzumab? Even in previously untreated patients, the response rates are only about 35 percent.

Dr Paik’s data showed rather conclusively that only in those patients whose tumors coexpressed cMYC and HER2 was a response to trastuzumab seen. Those data must be replicated, but if that were the case, this observation would be tremendously insightful.

Breast Cancer Update 2006 (8)

DR JENNY C CHANG: The bottom-line, take-home message from Soon Paik’s data was that if you have HER2-positive and cMYC-positive disease, you do very well with trastuzumab-based therapies. cMYC is an oncogene, and it was expected that if you had cMYC-positive disease, you would do badly.

In the adjuvant trastuzumab study, however, patients with cMYC-positive disease who received trastuzumab did extremely well. Their chance of relapsing was low — less than 10 percent, which was counterintuitive.

TOPO II is a different story. TOPO II is the target for anthracyclines. We also know trastuzumab in combination with anthracyclines adversely affects cardiac function and increases cardiotoxicity. The BCIRG wanted to determine whether any subpopulations of patients receiving trastuzumab could be spared therapy with anthracyclines.

As presented at the 2005 San Antonio Breast Cancer Symposium, the study demonstrated that, across the board, the nonanthracycline-containing trastuzumab-based regimen was not superior to anthracycline-containing trastuzumab-based therapy. The subset of patients with TOPO II nonamplified disease who received a nonanthracycline-containing regimen, however, did as well as the patients who received anthracyclines.

Breast Cancer Update 2006 (7)

DR TRIPATHY: In the next generation of clinical trials in HER2-positive disease, we’d like to improve the odds reduction. We would also like to use drugs that target other aspects of the HER2 pathway. A leading candidate is lapatinib, a dual HER1 and HER2 kinase inhibitor that also inhibits the same target, HER2, but in a different way.

It works on the cytoplasmic kinase domain, which is part of the signaling initiator. Some early data show a higher response rate when you combine lapatinib and trastuzumab. We already know from early pilot trials that previously untreated patients with HER2-positive disease show good response rates with lapatinib.

Bevacizumab with trastuzumab is also a reasonable combination to study. I would prefer to try to isolate the patients who will benefit, but without that, I do believe it’s reasonable. Some pilot studies also show that the bevacizumab/trastuzumab combination is safe and active. We have no randomized studies yet, but I believe that would be a reasonable place to look.

Breast Cancer Update 2006 (8)

DR LISA A CAREY: I consider HER2-driven breast cancer, in a biologic sense, as being at least two different groups. The HER2-positive, hormone receptor-negative group is different from the HER2-positive, hormone receptor-positive group.

They both benefit from HER2-targeted treatments, but they are different.

In terms of how HER2 functions, we’re obtaining a lot of information from the emerging studies of trastuzumab resistance and the pathways that are important in trastuzumab resistance.

The first issue — and I believe lapatinib speaks to this — is whether HER1 is important in acquired HER2 resistance. The studies of HER1 expression in de novo trastuzumab resistance have not been particularly compelling. They’re also not very big. The fact that lapatinib shows efficacy in patients with acquired trastuzumab resistance, I believe, provides a strong suggestion that the HER1 pathway may be implicated in getting around HER2 signaling. Tumor cells are smart, and they figure out ways to go around our therapeutic interventions. They co-opt nearby pathways.

One of the ways they co-opt is by using HER1. Similarly, instead of borrowing a neighbor to stimulate the same pathway, they can use a neighboring pathway that stimulates the same downstream molecules. That’s where the IGF1R data fit in, which do not so much indicate co-opting as simply a redundant pathway. Fortunately, several IGF1R, largely antibody-based therapies are entering clinical trials.

Breast Cancer Update 2006 (6)

DR GEYER: We are committed to collaborating with Dennis Slamon and the BCIRG jointly on the concept of adding bevacizumab to adjuvant trastuzumab. We have been waiting for their pilot data evaluating the combination of bevacizumab and trastuzumab as frontline therapy for patients with HER2-positive disease. The trial is progressing well, and from what they have been able to share, it looks as if this is something we definitely will be pursuing.

When patients’ tumors have HER2 amplification, a high percentage — about three quarters of the patients — also have upregulation of VEGF. Those patients do not do well when treated with chemotherapy alone — they have a strikingly poor outcome.

The assumption is that something is mechanistically driving the cancer, and if you shut down both of those pathways, you will improve outcomes. Preclinical models look very strong, and they were the justification for taking this into a clinical trial.

We are currently working on a straightforward concept evaluating trastuzumab versus lapatinib versus the combination using an AC followed by weekly paclitaxel template as neoadjuvant therapy. All the patients will receive that basic chemotherapy regimen, and the HER2 blockade will start with paclitaxel.

Then the patients will have surgery to determine the pathologic complete response rate. After surgery, all the patients will receive trastuzumab for one year. They will be receiving standard therapy with trastuzumab, but we will obtain baseline tissue and do the correlative work to see if we can determine which patients might do better with each of the drugs individually or in combination.

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