History

This vigorous, active and very healthy woman presented with a 2-centimeter tumor that was hormone receptor-positive and HER2-positive. Two of 14 lymph nodes were positive. Atorvastatin (Lipitor®) was the only medication she was taking.

Follow-up

She was treated adjuvantly with four courses of doxorubicin/cyclophosphamide followed by anastrozole, which was well tolerated.

Case discussion

I think the mindset that some physicians have is that 70-year-olds are “really old,” but a healthy 70-year-old woman can live another 15 years. A patient with several positive nodes has a very high risk of recurrence, and breast cancer may shorten her life.

Selection of adjuvant hormonal therapy

In patients like this one with HER2-positive disease (IHC 3+ or FISH-positive), there are specific reasons to consider an adjuvant aromatase inhibitor. As suggested by the molecular biology and preclinical data, women with HER2-positive disease may have some degree of tamoxifen resistance.

Additionally as patients get older, their risk of vascular disease generally increases. Tamoxifen probably does not substantially increase the risk above baseline, but it is a concern.

A positive HER2 status would lead me to consider an aromatase inhibitor in postmenopausal patients. I would also probably consider the implications on bone and get a baseline bone mineral density.

Treatment on relapse

If this patient presented two years later with hip pain, a bone scan that was positive in several areas, normal laboratory values and no evidence of other obvious metastases, I certainly would use another form of endocrine therapy. It would be reasonable to select tamoxifen, because she has not been exposed to it. Even though she has HER2-positive disease and that might make the response rate to tamoxifen lower, I would probably still try it.

Fulvestrant would also be a reasonable alternative. We really do not know about the influence of HER2 status on the response to fulvestrant. Theoretically, it may not be influenced because of fulvestrant’s different mechanism of action.

There is preclinical data suggesting that trastuzumab can reverse resistance to endocrine therapy. The CALGB will be conducting a clinical trial in women who develop a recurrence while on adjuvant tamoxifen, or shortly after stopping it. Those women will be randomized to trastuzumab alone or trastuzumab plus tamoxifen. The trial will determine whether tamoxifen resistance can be reversed by trastuzumab. There will also be similar trials with the aromatase inhibitors.

Use of bisphosphonates in patients with metastatic breast cancer

At the initial diagnosis of metastatic disease to the bone, I put patients on a bisphosphonate. These agents are all pretty much equivalent, but I think most of us are using zolendronate because short infusions are preferred over long infusions. There are differences in the potency of the bisphosphonates, but there are no convincing differences in their efficacy when used at the optimal doses.

Second-line therapy for recurrent breast cancer

In the first few months, endocrine therapy can produce a flare in markers, alkaline phosphatase, skin lesions and bone pain. If after six months of tamoxifen, however, this patient was having more hip pain and the bone scan had a few more lesions, I believe I would try further endocrine therapy if the symptoms were modest. Since chemotherapy is palliative, there is no rush to use it.

On the other hand, if the patient had a profound change in tumor biology, multiple new metastases, pain all over and substantial liver involvement, I would probably turn to chemotherapy. In the typical patient, however, the scenario is slower, and there is time to act. Therefore, I would try another endocrine therapy.

Fulvestrant would be a very good choice. One could also try a progestin, but I am impressed by the data comparing fulvestrant to anastrozole in patients who are refractory to tamoxifen. It is fascinating that fulvestrant, which prevents dimerization of the estrogen receptor, attacks the same estrogen receptor that was not effectively using tamoxifen as an antagonist. This means that the cancer is still endocrine-dependent.

Third-line therapy for recurrent breast cancer

If after four to five months of fulvestrant, the patient then developed a few more lesions but was still in pretty good shape, it would be reasonable to consider another aromatase inhibitor, such as exemestane. In a study by Lonning et al, exemestane was effective in women who were refractory to either letrozole or anastrozole.

Fourth-line therapy for recurrent breast cancer

If the patient’s bone metastases were rapidly progressing every few months, I think it would be reasonable to next use trastuzumab alone, trastuzumab plus a taxane, or perhaps trastuzumab plus vinorelbine. It would be rational to select a drug like capecitabine as well.

If the patient was not very symptomatic, I suspect there would not be great differences with any of those interventions. The response rates will certainly be higher, I suspect, for trastuzumab plus a taxane than for capecitabine. My personal approach, though, has been to use capecitabine in many of these patients.

If the patient certainly had any major progression, my bias would be to give trastuzumab plus chemotherapy. If the patient were somewhat reluctant about chemotherapy for any reason, single-agent trastuzumab would be an alternative. In Vogel’s paper, the time to progression and survival for single-agent trastuzumab was similar to those in the pivotal trial. Although it is not a fair comparison, the numbers look pretty good.

I am sensitive to the data from the trastuzumab pivotal trial, which demonstrated a survival advantage of about five months for trastuzumab plus chemotherapy compared to chemotherapy alone. The pivotal trial was not designed so that trastuzumab was given to all patients secondline after chemotherapy, which would have conclusively proven that there was an advantage to giving trastuzumab plus chemotherapy, together. I suspect I am a “contrarian” here.

* In those responding to treatment.

Derived from Osborne CK et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: Results of a North American trial. J Clin Oncol 2002;20:3386-95. Abstract

Howell A et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20:3396-403. Abstract