Trastuzumab as first-line therapy for metastatic breast cancer

I am not aware of any evidence supporting sequencing a non-trastuzumab combination followed by a trastuzumab combination in chemotherapy-naïve patients with HER2-positive metastatic disease. Rather, the pivotal trial comparing chemotherapy plus or minus trastuzumab showed improvement in response rate, time to progression and survival when trastuzumab was added. In addition, over 50 percent of the patients who did not receive trastuzumab initially, received it subsequently, and did not get the same survival benefit.

In patients with HER2-positive, ER-negative metastatic disease, single-agent trastuzumab is a reasonable first step. Both Chuck Vogel in the first-line setting, and Melody Cobleigh in second- and third-line settings, have experience with single-agent trastuzumab in patients with indolent ER-negative disease. In a trial of single-agent trastuzumab, the Sarah Cannon Cancer Center investigators saw a greater than 50 percent clinical benefit. Patients who crossed over to adding carboplatin and paclitaxel exhibited an increased response rate, but there is probably a subset of patients who could be treated with trastuzumab alone for a while to see how they do.

Single-agent trastuzumab versus trastuzumab with chemotherapy

The decision to use trastuzumab sequentially versus concomitantly with chemotherapy is based on issues such as extent of metastatic disease and the time between diagnosis and progression. In a younger, relatively asymptomatic patient with bone metastases and a good performance status, I don’t think there is compelling evidence to use both chemotherapy and trastuzumab initially. There is no randomized trial comparing sequential versus concomitant therapy in such a patient, but in other settings comparing sequential versus concomitant therapy with chemotherapy, concomitant therapy doesn’t do any better in terms of survival.

Certainly there are patients with metastatic disease in whom you feel chemotherapy is indicated, such as patients with significant visceral or lifethreatening disease. Given the positive results of the trials where trastuzumab was added to chemotherapy — improved response rate, time to progression and survival — my approach has been to give trastuzumab with the chemotherapy. Given our recent Phase III trial results, I would use the carboplatin/paclitaxel regimen.

BCIRG-006: Adjuvant trastuzumab trial

I am excited about the novel approach of BCIRG-006 for HER2-positive patients in the adjuvant setting. In this trial, patients in the control arm receive doxorubicin/cyclophosphamide followed by docetaxel. The second arm is the same doxorubicin/cyclophosphamide regimen, followed by docetaxel plus trastuzumab, continuing trastuzumab weekly for one year. The third arm is quite innovative in that it includes a taxane rather than an anthracycline. Patients receive trastuzumab, docetaxel and carboplatin or cisplatin for six cycles, followed by weekly trastuzumab for one year from the beginning of therapy.

This trial has an accrual goal of 3,000 patients and over 1,000 patients are already enrolled. It requires patients to be FISH-positive, which is probably the best predictor of interaction between trastuzumab and chemotherapy. I think the results will be quite meaningful to the future management of HER2-positive patients in the adjuvant setting.

Implications of the ATAC trial results for clinical practice

When I heard the ATAC trial data last year, I was impressed. It’s a large trial of more than 9,000 patients, and the disease-free survival benefit with anastrozole was credible. It was interesting that the combination didn’t work, but anastrozole certainly appeared superior to tamoxifen.

The results of the 47-month update show continued improvement in diseasefree survival with actual improvement in the hazard rate with time, which provides even more support for the use of anastrozole in the adjuvant setting.

Currently, I uniformly recommend anastrozole to my patients at high risk for recurrence. I also use anastrozole in patients who are experiencing problems with tamoxifen — severe hot flashes, weight gain or issues related to their uterine status. Occasionally, I have had patients on anastrozole who switched to tamoxifen because of arthralgias. Tamoxifen is still a reasonable choice in an older patient with a low risk of recurrence.

I have not switched a patient who was doing well on tamoxifen to anastrozole. I also have not used the other aromatase inhibitors outside of a clinical trial, because the data is with anastrozole.

Adjuvant trial of capecitabine/docetaxel

Under the leadership of Joyce O’Shaughnessy, we are conducting an adjuvant trial aimed at taking advantage of the biochemical interaction between taxanes and capecitabine. Doxorubicin/cyclophosphamide followed by docetaxel, the control arm, will be compared to the capecitabine/docetaxel combination. This trial is based on the US Oncology study that evaluated this combination in the metastatic setting and showed improved outcome, including survival, in the capecitabine/docetaxel arm.

The tolerability of the regimen is a real concern in the adjuvant setting, so we lowered both the capecitabine and docetaxel doses in the investigational arm of the adjuvant trial. Accrual has been good to date and we have some early toxicity data.

CALGB-9741: Dose-dense versus conventional adjuvant chemotherapy

The results of the dose-dense trial are exciting. We’ve looked at dose for a long time and the strategies studied — increasing cyclophosphamide from 600 mg/m2 to 2,400 mg/m2, increasing doxorubicin from 60 mg/m2 to 90 mg/m2 and giving high-dose chemotherapy in the adjuvant setting — were not successful.

However, dose density — giving the drugs every two weeks versus every three weeks — has translated into a disease-free survival advantage and, at this point, a survival advantage. I’m waiting to see more data, but I will present the results from the dose-dense trial to my patients, letting them know these are early results and there is some tradeoff.

Treatment algorithm for patients with metastatic breast cancer

Choosing a chemotherapy regimen for patients with metastatic breast cancer depends on the pace of the disease. If someone with indolent disease progresses on endocrine agents, switching them to another oral agent such as capecitabine is a very attractive option.

Capecitabine is generally well tolerated, especially now that we have improved dosing. We now begin with 1,000 milligrams per meter squared BID, rounding down as needed for 14 out of 21 or 28 days (two weeks on, one to two weeks off). In my experience, this regimen is both well tolerated and efficacious.

Combination chemotherapy is a consideration in patients with more aggressive disease. In a patient who’s had prior anthracyclines, a taxane or taxane combination (such as taxane/carboplatin), especially with the weekly schedule, is a well-tolerated and efficacious approach.

Use of fulvestrant in patients with ER-positive metastatic disease I’ve used a fair amount of fulvestrant, and I find that it’s well tolerated. Patients don’t have any problem coming in once a month for their intramuscular injections. In terms of efficacy, we’ve had patients experience stabilization of disease for six months. What is nice about fulvestrant is that it offers another option, especially for the patient who may be experiencing difficulty tolerating their current endocrine therapy.

Targeting angiogenesis in the treatment of breast cancer

Although it was disappointing that the response rates in the bevacizumab trial did not translate into time to progression, I would not get too discouraged. It reminds us that we need to know the target in order to target therapy. Chemotherapy covers a number of different tumor cells, and we don’t need to be as specific with therapy. But, imagine if we had done the trastuzumab trials without knowing to target HER2, IHC 2+ and 3+ patients — we would not have seen the benefits of the therapy. Tamoxifen is another good example of a targeted therapy; it works in ER-positive tumors, but it took us a long time to figure that out.

In order to target angiogenesis, we need to identify tumors in which angiogenesis is important, and we probably need to use a multiagent approach to hit multiple targets. Our increased understanding of the molecular biology of breast cancer has given us better insight, and we need to step up to the challenge of developing targeted strategies to take advantage of that biology.

EGFR inhibitors in the management of ER-negative breast cancer

We know from the NSABP P-1 study that in the high-risk population, tamoxifen reduces only ER-positive breast cancer incidence. Dr Craig Allred, in analyzing NSABP B-24, found that patients with ER-negative DCIS received no benefit from tamoxifen. What are the strategies available to treat ER-negative breast cancer?

The role of EGFR inhibitors in the management of patients with ER-negative breast cancer was discussed at the San Antonio meeting. First, one has to be certain that the immunohistochemistry is properly interpreted and the patient is truly ER-negative. Tamoxifen doesn’t work in that group, but could an EGFR inhibitor — like gefitinib — potentially work? Manipulating the EGF receptor tyrosine kinases is a potential approach, but additional research needs to be done in this area.

Participation of the elderly in clinical trials

I have a lot of respect for CALGB-49907 for both the trial design and the idea of recruiting the elderly for clinical trials. It will be interesting to see the results comparing capecitabine to standard regimens. US Oncology also has a trial for the elderly, comparing intravenous CMF versus weekly docetaxel.

When you look at previous trials, patients over 70 are underrepresented. The accrual in both of these trials is slow, which may just be the nature of treating an older population with other medical illnesses. Maybe their ability to tolerate chemotherapy is less, although there are studies that suggest that isn’t the case.

The number of eligible patients is probably smaller, and their ability to come in for treatment may be a barrier. While both of these trials are reasonable, the challenge is getting them done.

Development of a nonalopecia-causing breast cancer regimen

The US Oncology breast committee is seeking to develop a regimen that does not cause alopecia. While 20 years ago we had only a handful of drugs to work with, we now have a number of drugs that are not associated with alopecia — capecitabine, vinorelbine, gemcitabine, doxorubicin HCL liposome injection — and a number of combinations can be studied. It is worth noting that we don’t do a good job of recording alopecia in clinical trials, and we need better documentation.

It will take some time to find a successful nonalopecia-causing regimen in the adjuvant setting — we certainly won’t compromise survival to save hair. This is also important in the metastatic setting. Breast cancer is a very private matter, and alopecia makes it difficult to hide. Eliminating this side effect of therapy would make breast cancer treatment easier for patients.

Select publications

Return
Page 2 of 2

Home · Search