Edited excerpt from the discussion:

DR PROVATAS: This patient is a 59-year-old Caucasian postmenopausal woman who presented with a painful right breast to her primary care physician in February of 2003. She subsequently underwent a mammogram and was found to have a three-centimeter mass in the supralateral portion of the right breast.

She saw a surgeon and underwent a rightbreast lumpectomy. A 2.5-centimeter moderately differentiated IDC was found. The pathology revealed that the patient had 22 out of 29 lymph nodes positive, and the tumor was ER/PR-positive and HER2-positive 3+ by IHC.

I saw her afterwards in consultation, and she had not yet had a metastatic workup. I performed a workup and found her to have liver, lung and bone metastases. We biopsied the liver lesion and it came back HER2-positive, 3+ by IHC again.

DR LOVE: You told me that when you met with her, you were able to elicit a history of bone pain.

DR PROVATAS: That’s correct. She did mention subsequently that she had some posterolateral rib cage pain. It wasn’t clear whether she had presented that to her primary care physician or not, but when we conducted a bone scan, it did light up in the right posterolateral rib cage area. We consulted with a radiation oncologist, but she chose not to proceed with radiation.

DR LOVE: Tom, what are your thoughts about this case?

DR BUDD: For a patient who is not at high risk for recurrence, I don’t favor extensive staging studies. In someone who has had surgery and has 10 or more nodes, I agree entirely with going ahead with staging studies. If you look at data from the bone marrow transplant studies, approximately 20 percent of those patients with 10 or more positive lymph nodes have metastatic disease. However, I believe a good history, physical examination and so on should be adequate for most patients.

I don’t believe it’s criminal for this patient to have had this surgery. In fact, a retrospective study from the American College of Surgeons evaluated a database of patients with metastatic disease who underwent surgery (Khan 2002; [4.1]). The study showed that the patients who had more surgery had a longer survival.

Mastectomy seemed to be a little better than a partial mastectomy, which seemed to be a little bit better than no surgery. It was retrospective and probably more hypothesis generating, but I think it is an interesting insight that perhaps deserves to be followed up on.

In terms of treatment at this point, it is an interesting question. In 2005, we have two targeted therapies in breast cancer, but we still don’t have a clue about how to optimally sequence or combine them.

I think this is going to be a bigger problem as we hopefully come up with more targeted therapies and more targets for treatment. We will have to determine which target we should attack first or whether we should attack all the targets at once.

Several treatment alternatives could be justified here. One would be hormone therapy alone, probably with an aromatase inhibitor. Another would be hormone therapy plus trastuzumab. However, that is based on Phase II data only, which do show reasonable response rates (Marcom 2005).

Some people have said that so-called “super responders” exist with prolonged responses to treatment. But again, these are uncontrolled trials, and we don’t have Phase III data yet. Chemotherapy plus trastuzumab is also an option based on evidence of a survival advantage compared to chemotherapy alone (Slamon 2001).

Personally, in these cases, I tend to use an aromatase inhibitor first, depending on the volume of the liver disease. If the patient progresses, which many of them do fairly rapidly, I will go on to chemotherapy with trastuzumab.

DR LOVE: Can you talk a little bit about the extent of her liver disease and symptoms?

DR PROVATAS: Essentially, she was asymptomatic in terms of weight loss, and she didn’t have right upper quadrant pain. On CT, she had four to five lesions in the liver, and an MRI confirmed that she had at least five.

DR LOVE: Bob, can you talk about your approach to first-line therapy of women with ER-positive, HER2-positive tumors? Also, would you have FISHed the tumor?

DR CARLSON: With a HER2 overexpression 3+ by the Dako test, I would not normally have done a FISH analysis. I pretty much exclude FISH analysis except for the HER2 2+ by IHC.

For the treatment pick list, I would have looked at it exactly the same way as Tom just outlined — hormonal therapy alone, trastuzumab alone, hormones plus trastuzumab or chemotherapy plus trastuzumab. The breaking point for me would be related to the extent of her metastatic disease and how troubling it was to her. It sounds like she was minimally symptomatic and had relatively limited hepatic disease. I assume she also had minimal liver function abnormality.

DR PROVATAS: Liver functions were normal, but she did have at least 10 pulmonary lesions.

DR CARLSON: It’s always a tough judgment call. I most likely would have started with hormonal therapy. In California, just about every woman who walks in with a HER2 overexpressed tumor tells you that she also wants trastuzumab. So most of my patients in this context would get an aromatase inhibitor plus trastuzumab.

Alternatively, if I was concerned about her visceral involvement and thought that she was approaching a crisis point, I would typically use cytotoxic chemotherapy plus trastuzumab to maximal response, and I would then continue trastuzumab and add in an endocrine agent at that point in time.

DR LOVE: Dr Provatas, can you follow up with what happened?

DR PROVATAS: Given the fact that she had visceral disease, although asymptomatic except for the rib cage pain, we elected to go with docetaxel/trastuzumab for six cycles, three out of every four weeks. She had a great response, and all of her disease disappeared in the liver and the lungs. She did have a residual bone lesion in the rib, but we elected to switch and are now using letrozole, trastuzumab and zoledronic acid. She has been in remission since then.

DR LOVE: Bob, any more thoughts about this case?

DR CARLSON: That was a reasonable approach, especially if you were concerned about her visceral involvement. This is one of those situations in which having the ability to look at the CT scan to see what the lungs and liver look like would be crucial in the decision-making. However, the approach that was taken was reasonable, and obviously, you don’t want to argue with success.

DR LOVE: Dr Schwartz?

DR SCHWARTZ: How often do you dose trastuzumab in that situation? Because patients whom you have on an aromatase inhibitor and trastuzumab have no need to come into the office. Do you have them come in every three weeks or every week?

DR BUDD: In this situation, I’ve used every three-week treatment. We have two Phase II trials with every three-week dosing (Baselga 2005; Leyland-Jones 2003), and my personal experience is that these patients seem to do as well as you would expect. So because of convenience to patients, after they have been on treatment for a period of time, I will often go to the every three-week schedule.

DR LOVE: Bob, many people talk about matching the schedule of trastuzumab to the schedule of the chemotherapeutic regimen the patient will be on. I have even heard of people using every two-week trastuzumab. What are your thoughts about that?

DR CARLSON: I think convenience for the patient in terms of delivery of the therapy is crucial. One of the toxicities patients experience that we often don’t talk about in clinical trials and practice is the toxicity of actually going to the doctor’s office. Many patients don’t like that aspect of care, especially if they have experienced cytotoxic chemotherapy within our offices. It’s an anxiety-provoking encounter for them.

So in a woman like this who is getting a bisphosphonate and trastuzumab, I would typically put her on both agents on an every three-week schedule to try to minimize her time in our infusion center and number of visits to our office.

DR LUSKEY: Upon progression, if she were not in visceral crisis, what would you look at next?

DR CARLSON: Of course, an entire series of hormonal agents and a whole series of cytotoxic agents could be used. We also should not lose track of the fact that she had her docetaxel discontinued, not due to progression but rather because of such a good response. The pick list of agents is quite extensive in this woman.

I would typically use sequential single agents in terms of cytotoxic therapy; however, deciding which of those agents to go with next, I believe, is a matter of how impressive her response was to the taxane and the duration of control she experienced.

I also try to get a sense from patients as to which toxicities they are most concerned about. You can often avoid the one toxicity that may be most troublesome to the patient if you pick your cytotoxic agent correctly. However, this is a difficult issue, and we have little data on the optimal sequence of agents. We have a lot of data on which agents are active but not much data on the optimal sequence.

DR LOVE: One of the things we have seen in our Patterns of Care studies is an agreement between both the community physicians and research leaders when it comes to continuing trastuzumab. Approximately 90 percent of physicians we surveyed say they are usually continuing trastuzumab through at least two chemotherapies. Tom, how have you seen that issue evolve over the last few years, and where do you think it’s heading?

DR BUDD: I also tend to continue trastuzumab into at least second-line treatment, and if the patient responds well to that, I will then continue it into the third line also.

Of course, I recognize that we don’t have clinical trial data to support this approach (Tripathy 2004). As you may know, MD Anderson would like to open a trial looking at vinorelbine with or without trastuzumab in the second-line setting hoping to answer this question.

I certainly don’t think it is unethical to put a patient on that trial and randomly assign them to vinorelbine alone.

However, due to the long half-life of trastuzumab, that trial may be unavoidably confounded. In fact, patients receiving vinorelbine alone will be receiving the combination, at least for the first month or so. This is an important issue to analyze.

I also point out that while this type of approach is not what we usually use for the systemic treatment of malignancy, it’s not totally unheard of.

In the urologic community, it’s believed that androgen suppression should be continued indefinitely, based on retrospective, nonrandomized trials.

Other examples exist in which we continue treatment in the face of progression.

If you evaluate gastrointestinal stromal tumors, the standard of care is now to continue treatment in the face of progression because withdrawing treatment with imatinib mesylate seems to be associated with more rapid progression. That is another example in which we may continue an agent in the face of progressive disease.

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