Adjuvant trastuzumab in the nonprotocol setting

In the nonprotocol adjuvant setting, it’s hard to know the right thing to do. I’ve evaluated patients with high-risk disease — 10 or more positive nodes — in whom I’ve considered adjuvant trastuzumab therapy off protocol.

I don’t want to say that this is something that is widely done at our center — it’s infrequent and uncommon. However, the prospects for a patient with that type of disease are really unacceptable. If you consider that trastuzumab prolongs survival in patients with metastatic disease, biologically there are probably many similarities between high-risk Stage II and advanced disease. Therefore, that would be an interesting patient population to study, and off protocol we have considered such patients for adjuvant trastuzumab therapy.

Influence of trastuzumab therapy on tumor HER2 status

We don’t really know what happens to a patient’s HER2 status after they have been treated with trastuzumab. In the metastatic setting, some case series of preand post-treatment biopsies have been reported with conflicting results. Because most of the trastuzumab trials have been conducted in patients with metastatic disease, in whom it is difficult to obtain biopsies, there is no good database of pre- and post-treatment tumor tissues.

When HER2 gene amplification occurs, it appears to be a very stable event. Several studies have shown good concordance between the HER2 status in the primary tumor and the metastases. Given that level of concordance and the presumed genetic stability for HER2 amplification, I would be very surprised if trastuzumab could change HER2 gene amplification.

I suspect that if one rebiopsied a patient with residual tumor after trastuzumab therapy, one would find the HER2 gene still amplified. I would expect that the tumor’s genotype would probably not be changed whether the cancer was responding or resistant to trastuzumab. It’s just mind-boggling that we haven’t done that yet. We need to do a better job of obtaining tissue for laboratory analysis.

Trials combining trastuzumab with hormonal therapy

In preclinical models, we observed greater efficacy for tamoxifen plus trastuzumab and fulvestrant plus trastuzumab compared to each drug alone. The more we can do to constrain potential mechanisms of escape for the cancer cell, the better. If HER2 is a potential mechanism of escape from hormone sensitivity, then targeting both at the same time could work.

A number of ongoing trials are evaluating these combinations, and based on our preclinical data at UCLA, we think they might work. However, due to the inverse correlation between HER2 and ER, accrual to these studies has been difficult.

Fulvestrant in clinical practice

I’ve been pleased with fulvestrant and have not found the need to deviate from the package insert recommendations. In my experience, patient tolerance has been excellent with very few complaints about side effects. We’re using fulvestrant in patients who have already had prior hormonal therapies, so perhaps they don’t mention side effects because they are already used to the hormone withdrawal side effects.

I’ve certainly not had the occasion to stop fulvestrant in any patient because of toxicity. Compliance is very good, and the injection really isn’t an issue. These are highly motivated patients with a devastating disease, so they do not object to receiving an injection. I am using two 2.5 cc injections.

Potential synergy between fulvestrant and trastuzumab

HER2 does two different things to the estrogen receptor (ER). First, it decreases ER expression so there’s less ER in a patient with HER2-positive disease. Even if the tumor is ER-positive, it is less positive than a tumor from a patient with HER2-negative disease. Second, through cross talk between the signal transduction pathways for HER2 and ER, there is phosphorylation of the ER that may alter the biology of the receptor and result in an activated species. For that reason, it would be nice to eliminate the ER in a HER2-driven tumor. Fulvestrant, given its mechanism of action, provides a particularly attractive way to deal with the ER in a patient with HER2-positive disease. It’s an ideal model that works in preclinical xenograph models.

Trials combining trastuzumab with biologic agents

Erlotinib

We are especially interested in moving forward with biologic combinations. In fact, we have a couple of open trials at UCLA evaluating combinations of biologics. Dr Carolyn Britten is conducting a Phase I/II clinical trial with trastuzumab in combination with erlotinib, a small molecule inhibitor of the epidermal growth factor receptor (EGFR/HER1).

In this instance, we’re studying whether inhibiting HER1 and HER2 simultaneously might be better than just HER2 blockade alone. This may potentially allow fewer avenues of escape for the cancer cells. We hope this will be another improvement in the treatment of HER2, positive disease.

Bevacizumab

Based on measurements from our laboratory showing a strong correlation between HER2 and expression of the vascular endothelial growth factor (VEGF), a Phase I trial just opened at UCLA. A very strong concordance between HER2 and VEGF in primary breast cancer has been confirmed by other groups. Linderholm et al presented data at ASCO demonstrating the same thing in a very large data set. We’ve just completed a study involving about 612 patients with primary breast cancers showing this type of correlation.

Part of the pathophysiology behind HER2-driven disease may be regulation of the angiogenic switch. If we could address both of those problems, maybe we would see improved therapeutic efficacy. We’ve applied this theory in animal models using a combination of trastuzumab and the humanized anti-VEGF antibody, bevacizumab. In those studies, the combination had better results against murine tumor xenographs.

Based on these pilot data, we have a new Phase I trial that will be escalating the bevacizumab dose and using the standard FDA-approved dose of trastuzumab. When we complete the Phase I trial, it is designed to roll over into a formal Phase II trial to accrue more safety and efficacy data.

Treatment options for patients with ER-negative, HER2- negative, metastatic disease

This is a difficult subject, because it involves the controversy over combination chemotherapy and monotherapy. For the first time, the FDA has approved a combination chemotherapy regimen for metastatic disease, the docetaxel/capecitabine combination.

In appropriate cases, I think that combinations like this can’t be overlooked. In my practice, I’ve moved towards combination chemotherapy for patients with potentially life-threatening metastatic disease; otherwise, the off-protocol treatment for patients with ER-negative, HER2-negative disease involves sequential single-agent regimens.

Based on cross-trial comparisons of Phase II data, many single agents have very similar response rates and times to progression. Given the relative equivalence of capecitabine, vinorelbine and gemcitabine in patients who have failed a taxane and an anthracycline, I make decisions based on convenience and toxicity.

If patients have not been treated with an anthracycline or a taxane, I start with those first. But many of the patients that we’re seeing now with metastatic disease have already failed an anthracycline or a taxane in the adjuvant setting, and we have to consider moving on to different classes, especially if they’ve relapsed quickly.

If they’ve had a long disease-free interval, then we treat them with either a taxane or anthracycline. However, in the taxane and anthracycline failures, capecitabine really is a strong consideration because of its convenience for the patient.

Transition from hormonal therapy to chemotherapy

The transition from hormonal therapy to chemotherapy in metastatic disease maybe a little bit easier with capecitabine than with other agents. In patients with low-volume disease and no life-threatening metastases, capecitabine is an attractive option. We have used it in elderly patients in whom pulling out the “ big gun” intravenous drugs is a bit more problematic.

On the other hand, in patients who have marked progression, rising liver function tests and symptomatic pulmonary metastases, combination chemotherapy — like capecitabine/docetaxel — becomes more of a consideration.

Phase III trial comparing capecitabine with or without bevacizumab

It’s interesting how the trial was viewed. It was touted as being a negative study, which it was, since it failed to meet its primary endpoint. However, when looking at a dataset, it’s very important to see if there are any positive signals.

The response rate for the capecitabine/bevacizumab arm was significantly higher than for the capecitabine-alone arm. There must be some explanation for that, because there was a blinded response evaluation committee. One potential explanation is that the bevacizumab had a beneficial effect.

We might have missed a significant improvement in time to progression by virtue of the fact that these were heavily pretreated patients. Historically, there aren’t many drugs that have been shown to improve time to progression after anthracycline and taxane failure. This is a really difficult patient population.

ECOG-E-2100: Phase III trial comparing paclitaxel with or without bevacizumab

ECOG is conducting a large randomized trial comparing paclitaxel with or without bevacizumab as first-line therapy for patients with metastatic disease. I believe that there’s still hope for bevacizumab in metastatic breast cancer. Until I see the frontline trial, I’m not going to walk away from the concept of targeting VEGF with bevacizumab.

Our data demonstrates a correlation between HER2 and VEGF. The patients with the highest probability of responding to VEGF-directed therapy are the HER2-positive patients. A limitation of the ECOG trial is that patients with very high levels of VEGF might not be accrued to that trial.

Use of adjuvant dose-dense chemotherapy schedules

The new CALGB-9741 dataset are very provocative. The results must be explained, and they cannot be dismissed. Clearly, there was a statistically significant benefit for dose-dense chemotherapy compared to an every-threeweek schedule. Based on this interim analysis, the cooperative groups have decided to move to a dose-dense approach in their future and, in some cases, ongoing studies.

I would like to see confirmation in other clinical trials, and confirmatory trials are in progress, so we will have that data in the future. Off protocol, should we be taking this approach into consideration for the treatment of our patients? It is an attractive option for a patient with a high risk of recurrence (i.e., Stage II disease).

I have used the dose-dense approach in some patients, and I have tweaked the regimens a bit in some cases. For example, I have given four cycles of the anthracycline-containing combination with growth factor support and then used weekly taxanes without growth factor support in patients in whom growth factor use was an issue or in an elderly patient whom I didn’t want to have as much risk of neutropenia. Weekly taxanes are still a dose-dense regimen. In some instances, I’ve used the every-two-week schedule all the way through.

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