Duration of maintenance trastuzumab

I have a patient who received a three-drug combination including trastuzumab in 1998, just after it was approved. She took a break from therapy while she traveled, and the only therapy she received after the break was trastuzumab. It has been five years now, and while she probably doesn't need the trastuzumab, I can't convince her to stop it.

In our trial, we had two complete responders who took trastuzumab for a year and then stopped because they were tired of coming in for office visits. One took no additional therapy and the other was ER-positive and went on tamoxifen. Both patients relapsed four to six months later.

These are small numbers to use in deciding whether to continue trastuzumab indefinitely, but it is enough so that I don't feel bad keeping this one patient on therapy. When patients like this relapse, it's often difficult to achieve another response, so I favor continuing therapy.

Trastuzumab alone or in combination with chemotherapy in HER2-positive metastatic disease

When I see patients with newly relapsed metastatic disease, I use a score sheet to evaluate ER status, HER2 status, time to relapse, sites of disease and symptomatology. At the bottom of the score sheet, but not to be forgotten, are the patient's comorbid conditions. While we've had some good luck with single-agent trastuzumab in a few patients, I generally give trastuzumab with chemotherapy unless I'm sufficiently concerned about a patient's underlying condition such that I am fearful of giving them chemotherapy.

In patients in whom I gave single-agent trastuzumab, trying to spare them chemotherapy, the responses lacked durability. I've had more success using chemotherapy with trastuzumab, and then stopping the chemotherapy after four to six months. Generally, if a patient relapses with visceral disease, I give three to six months of a three-drug regimen, like paclitaxel/carboplatin/trastuzumab, and the odds of a profound response are pretty high. I then use maintenance trastuzumab.

Impact of ER status on treatment of HER2-positive and HER2-negative metastatic disease

In our study we looked at the data to determine whether a tumor's ER status influenced the benefit derived. While the numbers in this trial are small, when we compare this data to data from other breast cancer trials, it is clear that many patients with ER-positive disease respond just as well to the trastuzumab as those with ER-negative disease, but it would be nice to know if it is worthwhile to add a hormone.

In patients with HER2-negative, ER-positive disease, I usually try to use as much hormonal therapy as possible before going to chemotherapy, unless they are rapidly progressing. However in patients with HER2-positive, ER-positive disease, I tend to give them hormonal therapy after they complete chemotherapy.

Paclitaxel/carboplatin/doxorubicin in the treatment of metastatic breast cancer

In HER2-negative patients, we've tried the combination of paclitaxel/carboplatin/ doxorubicin, replacing cyclophosphamide with carboplatin to take advantage of carboplatin's toxicity profile. With that combination, our response rate was approximately 55 percent, but there was a lot of toxicity. We compared our data with what Dr David Loesch reported for paclitaxel/carboplatin weekly and Dr Perez's data for paclitaxel/carboplatin given every three weeks, and we learned that doxorubicin just added toxicity.

Trastuzumab in first-line treatment of HER2-positive metastatic breast cancer

Some physicians do not include trastuzumab in first-line therapy for HER2-positive metastatic disease. I consistently hear colleagues talk about "saving" a drug or regimen. That may have been a reasonable strategy 10 or 15 years ago, but with the emergence of multiple taxanes, vincas and the topoisomerase inhibitors, I don't see a reason to save anything. It makes more sense to obtain your best response and then give the patient a break.

I tend to give at least two trastuzumab-containing regimens before bailing out. Just as in endocrine therapy, we assume that if the patient responded to one therapy, she is likely to respond to another. We know that the oncogene present in HER2-positive patients doesn't go away from primary disease to metastases, so it's more likely that they're acquiring resistance to the chemotherapy than to the trastuzumab. If the patient does progress on the second trastuzumab combination, sometimes I'll have the pathology checked, but often I'll move on to a different regimen and possibly even consider reintroducing an anthracycline.

HER2 assessment: Correlation between FISH and IHC results

Clearly, IHC is not perfect. I look at this very clinically. If the IHC result is zero, I don't worry about it, and if it is 3+, I treat it as positive because I know there is a 90 percent concordance with FISH-positivity. It's the IHC 1+ and 2+ cases that I look at carefully.

I'm very quick to order a FISH test on an IHC 1+ or 2+ tumor that I'm unsure about. The concordance rates with FISH are approximately 40 percent for IHC 2+ tumors, and 10 or 15 percent for IHC 1+ tumors. I have had several patients whose tumor was 1+ by IHC and FISH-positive. Twenty percent of women with HER2-overexpressing breast cancer fall into the IHC 0 or 1+ category. FISH may cost $200, but if it were my wife or sister, I'd certainly tell her to have the FISH test done.

Capecitabine in patients with HER2-positive tumors and brain metastases

The brain is a common site for metastases. A European abstract presented at ASCO reported how well patients with brain metastasis did overall and encouraged physicians to be aggressive in this group of patients. We need to look at agents that cross the blood-brain barrier for those patients, such as capecitabine.

One of my partners switched a patient from docetaxel with trastuzumab to capecitabine, because she developed a brain metastasis, and she had a great response. As patients live longer, we're going to see more metastases to the brain, and we need to learn more about treating those patients.

Sequential versus combination chemotherapy in the treatment of metastatic cancer

The question of whether sequential or combination therapy is superior in metastatic cancer is still unanswered. Many interpreted ECOG-1193 as being negative for the combination approach, but I don't totally agree. The combination was superior in response rates and time to progression, and it's difficult to show a survival advantage in a crossover trial. Community oncologists want a dramatic response for their patients.

We find when we put out a single-agent Phase II trial in our network, accrual occurs slowly, but if we design a trial with an exciting combination, accrual moves quickly. You can argue about survival curves, but they're all going to meet someday, and the quality of life is important. That's what I always tell my patients, but every patient we see in the clinic is different.

Fulvestrant in the treatment of metastatic breast cancer

We've used fulvestrant in the metastatic setting for a number of different scenarios, including patients who have progressed on aromatase inhibitors, those who request it for economic reasons, and in patients who don't like dealing with pills - they come in once a month for their bisphosphonate and their fulvestrant injection.

We have observed and heard from others that sometimes the best response with this agent is two or three months down the road. We have not had any problems with side effects or toxicities with fulvestrant. Pain at the injection site is perhaps the only issue, and I believe it is because we have an older population of women who may not have the body habitus to receive the injection without difficulty.

Progress in the treatment of breast cancer

I'm encouraged by the progress we are making in breast cancer. I can remember when the trastuzumab pivotal trials were under way, and the endpoint was time to progression because we didn't expect to see a survival advantage. But, lo and behold, we observed a survival difference. Then we looked for a time to progression endpoint for capecitabine/docetaxel, because there was no way we could show a survival difference. And, sure enough, this combination demonstrated a survival difference.

While we get a little confused about combination versus sequential therapy and how aggressive to be in the adjuvant setting, the bottom line is that things are really going very well. We have many patients living a long time with metastatic disease, and it's encouraging that it is taking a while to see the relapses in some of these adjuvant trials. We want to see the data, but, on the other hand, it's nice that three, four or five years later we still don't have enough events to make a call.

Clinical use of adjuvant taxanes

A commonly asked question is: Should every patient receive a taxane in the adjuvant setting? First we need to decide who should still receive CMF. Most of us don't administer CMF as Bonadonna and the Italians did; we give a watered-down version.

Many oncologists have switched to utilizing AC and now they are looking at incorporating a taxane - TAC, AC followed by T or the dose-dense approach. I believe that the vast majority of patients whom you want to treat aggressively should receive a taxane. In my patients at low risk, I still use AC, but in my patients at either moderate or high risk, I use a taxane combination.

ATAC: 47-month update and the impact on clinical practice

When the ATAC data were first reported and the ASCO committee issued their Technology Assessment recommendation that we stay with tamoxifen, there was a great deal of backlash from physicians who felt like they didn't want ASCO telling them what to do with that particular issue and that every patient was an individual.

I personally have fallen on the side of looking for an excuse to give an aromatase inhibitor in those patients. I've seen my own numbers go up from when I was probably using 90 percent tamoxifen, to gradually work down to where I'm probably giving one in three tamoxifen and two out of three anastrozole. I was also impressed with the data on bisphosphonates to prevent bone loss. I am quick to use a bisphosphonate or consult an endocrinologist.

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