Edited excerpt from the discussion:

DR WERTHEIM: This 41-year-old patient was referred to me by a local breast surgeon in May 2002 for consideration of neoadjuvant therapy. She had a relatively large — at least four centimeters — right palpable breast mass, with a palpable lymph node at least one centimeter in size.

Her biopsy revealed Grade II invasive ER/PR 3+ positive, HER2-negative ductal cancer. I elected to give her neoadjuvant chemotherapy with AC times four and docetaxel 100 mg/m² times four.

She had an excellent clinical response and underwent a lumpectomy with axillary dissection. Surprisingly, she had extensive lymphadenopathy and had 11 out of 26 nodes still positive. She had locally residual disease also, but the number of lymph nodes was very surprising to me.

DR LOVE: Was she working, and what was her family situation?

DR WERTHEIM: She was a homemaker and a mother of one. I’m actually friendly with her husband outside the office.

DR LOVE: How did she tolerate the chemotherapy?

DR WERTHEIM: Very well. She did have some significant leukopenia, and I administered pegfilgrastim with the chemotherapy.

DR LOVE: After seeing such a dramatic clinical response, you were probably surprised when you saw the pathology.

DR WERTHEIM: I was really surprised. The patient and her surgeon were very surprised. We were all taken aback.

DR LOVE: The reflex, particularly in a young patient like this, is to use neoadjuvant chemotherapy, yet she does have an ER/PRpositive tumor. Skip, you see a lot more use of neoadjuvant hormonal therapy in Europe (Dowsett 2003). Is that something you think that we’re going to be moving more towards in the United States, both off protocol and in clinical trials?

DR BURRIS: It’s something we need to consider more. The Europeans have shown very good early responses with hormonal therapy. I think, in this country, it’ll naturally start and be adopted more readily in older patients. I’ve done it in several women over the age of 65 to 70. Carlos Arteaga at Vanderbilt is doing some “window of opportunity” trials with letrozole and some of the new biologics and getting really impressive results with a few weeks of hormonal therapy. There are impressive data for the benefits of hormonal therapy.

I was jotting down things you would consider for a patient like this, and the common question of, “Oh my gosh. What would you give her for chemotherapy next?” The most important thing we may do for this woman is adequate hormonal blockade — to the most that we can achieve — with her consent.

DR LOVE: I’m very curious about your thoughts about hormonal therapy at this point. She was still menstruating at that point?

DR WERTHEIM: She stopped menstruating during the chemotherapy but restarted menstruating afterwards.

DR LOVE: Skip, what specifically would you offer her at this point?

DR BURRIS: At this point in time, with so many years away from achieving a natural menopause, I would strongly encourage her to consider an oophorectomy or the option of receiving an LHRH agonist once a month. If she elected for the oophorectomy, I’d administer tamoxifen during that time and then shortly thereafter sequence over to an aromatase inhibitor.

DR LOVE: You’d give her tamoxifen and ovarian suppression or ablation?

DR BURRIS: I believe that in premenopausal women — and certainly there’s folks who are much more expert at this than I — there is a period of time before they actually quit secreting estrogen and they still have circulating estradiol. So we follow their levels, and I would still continue to throw the maximum hormonal blockade at her. While I got her through the oophorectomy in the next several months, giving her tamoxifen in that setting would be part of my treatment plan.

DR LOVE: What about further chemotherapy?

DR BURRIS: This is a patient with whom I would go the extra mile in trying to decide which chemotherapy to use. There are mechanisms to have the tumor checked to see thymidylate synthase (TS) expression. If this patient had low levels of TS in her tumor, that would be a vote for utilizing capecitabine. For a very young woman with whom you’re trying to have a more aggressive treatment approach, I would certainly discuss capecitabine for an additional six months.

If her TS levels were very high and we were unlikely to get a benefit from that sort of treatment, vinorelbine would be another agent I would consider. Clearly, no data support that approach, but with 11 positive lymph nodes, my concern about residual tumor cells would be quite high. Having said that, 80 percent of the benefit will come from hormonal therapy.

DR LOVE: Mark, what are your thoughts about a patient who received neoadjuvant AC and a taxane and still has residual disease and multiple positive nodes. Fortunately, this woman had an ER-positive tumor, but how would you approach this situation if her tumor were ER-negative?

DR PEGRAM: When I see cases like this, I pray they will be ER-positive, so I don’t have to get into this sticky situation about whether or not to administer additional chemotherapy. No study has shown that additional chemotherapy, beyond the eight cycles that this patient received already, would be of any clinical benefit.

You could argue that the response she had indicates that she’s chemoresistant, and the natural history of her disease will probably not be changed by any other salvage agent that you elect to use postoperatively.

I’m pleased that this patient’s tumor was ER-positive. Having said that, for ER-negative cases, I have to admit that at UCLA when we see these cases, we do kick this around on our tumor board, and on some occasions, we have given patients three months of weekly vinorelbine or a few cycles of CMF or capecitabine. We have done that knowing full well that it may be useless. I just don’t know the answer, since there is no randomized trial to really address this question.

This is the kind of trial that really does need to be performed to answer the question of whether or not there is a salvage regimen that could be of benefit in this patient population. I discuss chemotherapy with patients like this, but I tell them there’s no evidence it will be helpful.

DR LOVE: Mark, which hormonal therapy would you utilize?

DR PEGRAM: I would tell her that tamoxifen remains the standard of care, pending results of ongoing randomized trials, which will compare ovarian ablation plus AIs versus standard hormone treatment.

On the other hand, I would certainly talk to her about ovarian ablation. One of the advantages of administering additional cycles of chemotherapy, particularly if it contained an alkylator, is that you could hope that she would finally go into menopause with more chemotherapy.

I would definitely discuss with her the randomized trials underway to compare an aromatase inhibitor plus ovarian ablation. That would certainly be a very reasonable option for her at this point, although I can’t say that it’s been established as a standard of care.

One issue that stands out in my mind in the AI versus tamoxifen studies is that many of the relapses occur within the first couple of years, which will be missed if you start with tamoxifen and switch to an AI. This patient’s relapse risk will certainly be high in the first two years, and maybe you can change that by starting with an AI plus ovarian ablation. I throw it out as a point to consider, but I don’t have the answer as to whether sequential use of AIs might still be better than starting out up front.

DR LOVE: Dr Wertheim, can you follow up to the present time with this patient?

DR WERTHEIM: She received radiation therapy followed by tamoxifen. Initially, I was very comfortable, and then she began menstruating again about four months into tamoxifen. We sat down and had a long discussion. I was very uncomfortable with her menses resuming, and I put her on some goserelin and tamoxifen at that time.

DR LOVE: In the premenopausal patient at high risk with ER-positive disease, we see in our Patterns of Care study that tamoxifen is certainly still the most common choice. Ovarian suppression plus tamoxifen is the next most common choice, and an increasing number of physicians are using ovarian suppression plus an aromatase inhibitor in spite of the fact that we really don’t have any data at this point.

DR LAMBERT-FALLS: As a female, I used to be totally against oophorectomies. I am becoming a proponent of oophorectomies because I can be certain the ovaries are blocked and the woman goes into menopause. I check their estradiol levels to make sure, because I have been burned once after the surgeon left behind a little piece of ovarian tissue. You have to be very careful with your levels.

DR PEGRAM: Absolutely, your point is well taken. There are numerous means of achieving ovarian suppression, and surgery is very effective, as long as they remove all of the tissue. Checking levels is always a good idea.

DR DRESDNER: One question about the LHRH agonist: Although monthly goserelin appears to be the only agent with an indication and leuprolide acetate monthly, does anyone use three monthly, and why not?

DR BURRIS: There’s no approval for it for on an every three-month schedule, and from what I’ve heard premenopausal patients will break through, so I’ve only used it monthly.

DR PEGRAM: That’s correct. Monthly administration is the preferred regimen for ovarian suppression.

DR BURRIS: The only data for every three months are with prostate cancer patients.

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