Meet The Professors VOL 4, ISSUE 1

Edited excerpts from the discussion:

DR DRAGON: This is a 76-year-old woman who presented with a left breast cancer. She was treated with mastectomy in April 2005 because of extensive positive margins at lumpectomy.

At the time of mastectomy, she had a residual 1.9-centimeter, Grade III infiltrating ductal carcinoma with one of two positive sentinel lymph nodes and 14 additional lymph nodes, which were negative. Estrogen receptor was 3+, progesterone receptor was negative, HER2 was 2+ by immunohistochemistry (IHC) and positive by FISH.

She was a very nice, deferential European woman who came in with her husband. They spoke English but with some difficulty. She deferred mostly to her son, a general internist, and he acted as her advocate during the entire discussion of her therapy.

DR LOVE: Dr Dragon, this woman was treated in the first trastuzumab window, after the initial presentation of the three trials at ASCO (Perez 2005; Piccart-Gebhart 2005; Romond 2005) but before the initial data came out from the BCIRG TCH trial (Slamon 2005; [1.1]). Could you describe her reaction to the discussion of therapy?

DR DRAGON: She was very resistant to being treated with chemotherapy. Although she was in excellent health and had never had any significant medical issues, except for some treated hypertension, her son was very concerned about giving her anthracyclines. He was aware of the reported interaction with anthracyclines and trastuzumab and their impact on cardiac function. So the idea of chemotherapy treatment met a lot of resistance.

DR LOVE: Did she have personal experience with other people who had received chemo therapy?

DR DRAGON: She had some friends who had received chemotherapy. Like most people, she recognized that the side effects could be significant, and she was very concerned about that.

DR LOVE: Cliff, suppose this woman presents to you for a second opinion about her adjuvant therapy? How would you discuss the various options with her, including trastuzumab without chemotherapy?

DR HUDIS: This is a tough case. All of the trials enrolled very few patients above age 70. The BCIRG trial capped entry at age 70.

This is an issue because globally — at least when you go back to the overview analysis — the marginal benefit of any chemotherapy versus none in women above age 70 is not established. I believe a benefit exists, but it’s not established for a variety of reasons, including the small numbers of patients in that age group placed in randomized trials. Largely, the impact is somewhat modest and clouded by the ER status and hormone therapy benefit in that age group.

So the problem I have with the case is that I don’t know what’s leading the decision. Based on a HER2-positive, node-positive breast cancer, independent of ER status, I would recommend an anthracycline-and taxane-based adjuvant therapy regimen to this patient.

I’m not sure she’s wrong to essentially insist on just an aromatase inhibitor and trastuzumab. We don’t have any data for that at all, but the marginal contribution of the chemotherapy to her outcome in this setting is speculative. We have absolutely no data.

DR LOVE: Have you treated any patients with adjuvant trastuzumab monotherapy?

DR HUDIS: I have not, but if I’d ever be tempted, it would be for an older patient with a high degree of ER positivity. Data for such cases are desperately needed and would fill an important gap. Frankly, to back up even a half step, the remarkably consistent impact of trastuzumab raises the question of the contribution of the chemo therapy.

DR LOVE: Dr Mackey, how would you have thought through this case?

DR MACKEY: We don’t have good evidence that chemotherapy is warranted, because of her age. But again, we have no evidence that trastuzumab is beneficial in the absence of chemotherapy. I hope this question will be enlightened by a trial you’ll be hearing about soon, called the TAnDEM study (1.2).

It’s a metastatic study in which the women with ER-positive, HER2-positive disease all received anastrozole and half were randomly assigned to receive trastuzumab. We’re waiting for three more events to do the analysis, so we expect the answer in 2006. It might inform this discussion to say whether or not anything is gained with the addition of trastuzumab to an aromatase inhibitor.

DR LOVE: Dr Mackey, in general, what are acceptable adjuvant treatment options for women with ER/PR-positive, HER2-positive disease?

DR MACKEY: Acceptable options include regimens from all of the trials: HERA, the NSABP/NCCTG combined analysis, or the experimental arm of BCIRG 006. There’s no reason that you would necessarily want to pick one over the other, but if you are going to treat a postmenopausal woman with ER-positive and HER2-positive disease, I’d suggest that you consider an up-front aromatase inhibitor strategy after completion of the chemotherapy. Certainly, in the absence of trastuzumab, there are reasons to believe that tamoxifen may not be as effective as an aromatase inhibitor (1.3). In the presence of trastuzumab, that’s still an open question.

DR LOVE: Bottom line: What would you have recommended to this patient?

DR MACKEY: If she had 45,000 Canadian dollars in her back pocket and very much wished to proceed, we could get her treatment with an aromatase inhibitor and trastuzumab off trial in Canada. We only fund what’s been proven by Phase III studies, so she would not be eligible for public funding. I would still monitor her cardiac function, as if she had received chemotherapy.

DR LOVE: Regarding the TOPO II data (Press 2005), which are so fascinating and one of the most interesting things that happened at this past San Antonio meeting, Cliff, would you consider the assay results if it had been done?

DR HUDIS: My default, if I am going to give chemotherapy, is to include the anthracycline.

DR LOVE: So if her TOPO II was low?

DR HUDIS: I think that you have to regard that analysis as interesting and provocative but not yet definitive. I would not be prepared, on a routine basis, to omit the anthracycline. On the other hand, for a patient with an elevated cardiac risk and a HER2-positive tumor, certainly, finding a lack of amplification would reassure me that carboplatin/docetaxel and trastuzumab is a great choice for her, although I’d probably choose it even if I didn’t know the TOPO II status, based on the cardiac risk.

DR LOVE: Dr Mackey, is TOPO II ready for “prime time?”

DR MACKEY: I don’t think so yet, although the data suggest that we may finally have a third predictive assay in breast cancer. We have ER to tell us whether we should be using hormonal therapy, and we have HER2 to tell us whether we need trastuzumab.

My prediction is that TOPO II amplification will become a validated predictive assay for benefit from anthracyclines, but we haven’t proven that yet (1.4).

We have data from a 2,000-patient subgroup of a 3,000-patient trial analyzed now, and I would like to see more events in the analysis. That will happen in the first quarter of 2007, when data from the full 3,000-patient trial population have been analyzed.

DR LOVE: Dr Mackey, have you treated any patients with adjuvant trastuzumab without chemotherapy?

DR MACKEY: Once, against my better judgment and my recommendation, but the patient insisted.

DR LOVE: Dr Dragon, would you follow up on what happened to this patient?

DR DRAGON: My thinking was very much in line with what the faculty mentioned. Based on the experience to date, demonstrating that a taxane with trastuzumab in the metastatic setting was better than single-agent trastuzumab, I convinced her to consider trying weekly paclitaxel and trastuzumab followed by an aromatase inhibitor.

Based on my reassurance that this would not be difficult, she was accepting and willing to take this therapy. So we started weekly paclitaxel and, much to my chagrin, within four weeks she had developed significant hypersensitivity problems, with a skin rash, fever and pulmonary symptoms. She was treated with steroids, and I had to discontinue the paclitaxel. We then continued on with the trastuzumab alone and anastrozole.

DR LOVE: How is she doing at this point?

DR DRAGON: She feels well and is asymptomatic. It took two to three weeks to resolve her hypersensitivity reaction, but since then she’s done very well on the trastuzumab and anastrozole.

DR MACKEY: This shows how we’re “skating on thin ice” in the absence of evidence. If something goes wrong, we can always be held to account with criticism from our colleagues as to why we bothered in the absence of proven benefit. I don’t disagree with anything that was done. It’s a difficult situation we all face.

Unfortunately, we don’t have trials to answer all of these questions, and we have to fall back on very good communication and documentation of the discussions when we enter into an arena that is not evidence based.

DR ASTROW: Dr Mackey, you mentioned the issue of funding in Canada, and a Finnish trial presented at San Antonio used a shorter course of trastuzumab. Is this something that you might consider in Canada?

DR MACKEY: The FinHer trial was really interesting (Joensuu 2005). It enrolled approximately 1,000 Finnish patients, and the 20 percent with HER2-positive disease were randomly assigned to a trastuzumab-based regimen or not. Two possible chemotherapy combinations were used, one with docetaxel and the other with vinorelbine.

The exposure to trastuzumab was nine weeks as opposed to 52 weeks. It does look as if the magnitude of the effect is approximately the same as that seen in the other adjuvant trials, if you combine it with docetaxel. The problem is that this is such a tiny trial, with only 200 patients. We can’t be comfortable that we know the true safety signal or that the efficacy signal is as real as it might appear. The p-value is 0.01 for disease-free survival, but we’re looking at really robust data from other regimens.

We believe a study of short-versus long-term trastuzumab is warranted, and that’s the biggest message from this trial. I don’t believe anyone will be adopting it as the standard of care.

DR KUZUR: My question is about the TOPO II test. Is it available commercially?

DR MACKEY: TOPO II tests have been available in several kits for laboratory use, but they’re not FDA approved.

Nonetheless, I believe some smart person will come up with a kit that tests both HER2 and TOPO II at the same time with different colors, and, presumably, that kit will be available soon.

I do not routinely order the test. The data are sufficiently preliminary that I’m not yet using it to make clinical decisions. I’d like to see it validated in larger sets.

DR HUDIS: I can’t help but point out that topoisomerase has been observed in other studies and has not delivered the same clean signal.

In a dose-escalation study of doxorubicin, topoisomerase inhibitor levels were not associated with a benefit from the higher-dose anthracycline, for example. I’m underscoring John’s point that we do need to see some independent corroboration.

Select publications