Monica Morrow, MD Professor of Surgery Northwestern University Feinberg School of Medicine Director, Lynn Sage Comprehensive Breast Program Northwestern Memorial Hospital

Edited comments by Dr Morrow

The significance of micrometastatic disease

The increasing use of sentinel node biopsy has raised a whole new set of questions, including whether micrometastases detected by immunohistochemistry are clinically significant. This is a biologically interesting question, and I strongly agree with the College of American Pathologists’ consensus statement that we do not yet understand the meaning of these micrometastases. The retrospective studies of micrometastases have been a “mixed bag,” including patients who have large areas of missed tumor in their lymph nodes and patients with small numbers of cells in subcapsular sinuses that aren’t even in the node parenchyma. It’s not particularly surprising that some of these studies show no survival difference, some show small survival differences, and some show very big survival differences.

This is an area where both the NSABP-B-32 sentinel node study and the American College of Surgeons Z-10 study will provide us with very important information. Until that information is available, we use immunohistochemistry only if there’s diagnostic uncertainty on the basis of something seen on an H&E stain. We do not routinely perform immunohistochemical staining of sentinel lymph nodes because we don’t know what to tell the patients.

Clinical use of adjuvant aromatase inhibitors

The follow-up data with anastrozole from the ATAC trial look good and suggest that the bone problems may be reaching a plateau, which is encouraging. For women with low-risk, ER-positive, HER2-negative breast cancers with very favorable prognosis, we still use as much tamoxifen as anastrozole. For women with HER2-positive breast cancers, I favor an aromatase inhibitor because of the debate as to whether overexpression of HER2 predicts resistance to tamoxifen.

If the patient’s prognosis is less favorable, I would be more likely to treat her with an aromatase inhibitor. There is clearly a greater benefit from anastrozole compared to tamoxifen in the short term. In a patient whose risk of relapse is quite high, the absolute difference between these two treatments is much larger. I would favor an aromatase inhibitor in this setting, and the data we have right now in the adjuvant setting is with anastrozole.

Aromatase inhibitors for chemoprevention and DCIS

The question about aromatase inhibitors as preventive agents is a very important one. I am concerned that the IBIS-II trial — comparing anastrozole to placebo — won’t give us the answer we need. We’ll know if anastrozole is better than a placebo but we won’t know how SERMs compare to aromatase inhibitors or which is better in terms of overall health. We will not be able to extrapolate these answers from two completely different study populations, and this will leave us with another trial to do. In addition, I would not recommend this trial to a woman at very high risk. With tamoxifen on the market, proven to reduce breast cancer risk, I don’t think taking a 50 percent chance of being randomized to a placebo is a good choice. IBIS-II also has a randomization for women with DCIS, but this compares anastrozole to tamoxifen. I agree that treating DCIS is prevention — it’s a lesion that carries a significantly increased risk of invasive breast cancer. We tend to think of it differently because we treat it like cancer, but the question is the same. The NSABP-B-35 trial is asking the same question, randomizing women with DCIS to anastrozole versus tamoxifen. It is a very good trial, addressing a very important question, and I heartily support that study.

Management of the primary breast lesion in women presenting with metastatic disease

I have traditionally thought that we should only treat the primary tumor if it was progressing and causing local problems; however, last year my colleague Seema Kahn and I published a study in the Journal of Surgery of 15,000 women who presented with metastatic disease from the National Cancer Database of the American College of Surgeons.

We looked at differences in survival based on surgical treatment of the primary lesion versus no surgery. This was based on tumor registry data. We controlled for a number of documented metastatic sites and visceral versus soft tissue, and we found a very consistent pattern wherein surgical treatment of the primary lesion was associated with improved survival. While there may be selection bias to some extent, the differences were seen in all subgroups.

This study raises some questions as we develop more effective systemic therapy and keep people alive longer: Does it make sense to reduce the tumor burden maximally so there are fewer places the treatment has to work? We see this in renal cell carcinoma for example, where removal of the primary tumor results in survival differences. I think it’s an open question. However, removal of the primary lesion is a reasonable option to try to maintain local control and prevent morbidity, even if it doesn’t improve survival. If the patient is clinically node-negative, I don’t see that there’s a lot to be gained by dissecting the axilla.

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