Re: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes.

With the advent of screening, an increasing proportion of newly diagnosed breast cancers are 1 cm or less in size (stages T1a and b), and an emerging dilemma is addressed in the article by Fisher et al. (1). As pointed out by Lippman and Hayes (2) in their accompanying editorial, there is no biologic rationale for expecting any qualitative difference in efficacy of adjuvant systemic therapies between smaller tumors and larger/lymph node-positive tumors. A tumor requires a blood supply to grow beyond the size of a few millimeters (about 1 million cells) (3). Neovascularization generates endothelium, which is fragile and leaky, and cancer cells can readily break away from a tumor bolus to enter the circulation via highly permeable new blood vessels. The potential to metastasize, therefore, exists from the nascent phase of tumor development and provides mechanistic support for Fisher’s hypothesis that breast cancer is a systemic disease at the outset for many patients. Adjuvant therapy is ostensibly indicated whenever micrometastases are present. Patients without micrometastases do not require adjuvant treatment by definition and are cured by locoregional treatment alone. Of those patients with micrometastases, there is an implicit gradation in prognosis and response to adjuvant therapy dependent on the micrometastatic load. Fisher et al. have highlighted the nuances of pathologic size determination. Although maximum tumor diameter is a prognostic factor, grade (histologic and nuclear) and lymphovascular invasion are strong predictors of outcome, and neither of these variables were analyzed independently by the authors. Of interest, stratification of patients according to estrogen receptor (ER) status revealed no statistically significant benefit for chemotherapy with respect to disease-free, event-free, or overall survival, with a hazard ratio of 1.28. A type II error may have occurred in this analysis, which was based on small numbers of ER-negative patients, although even with ER-positive tumors, statistically significant benefit for chemotherapy was confined to overall survival (hazard ratio 0.40). Approximately equal numbers of patients analyzed underwent mastectomy or breast conservation. It would have been interesting to analyze the relapsefree survival (RFS), event-free survival (EFS), and overall mortality for these two surgical groups and to have incorporated this subdivision into analysis of benefits of systemic treatment; historically, mastectomy was rejected as standard treatment of breast cancer because of its lack of impact on mortality rather than influence on local recurrence rates. Mastectomy has never been evaluated for tumors of 10 mm or less, but improvement in DFS or EFS per se would not justify mastectomy for this group. Similarly, recommendations for systemic therapy should not be based on the inappropriate end points of RFS and EFS. Patients must make individual decisions about systemic chemotherapy once fully informed about the likely benefits and side effects of treatment. According to the paradigm of biologic predeterminism, all patients should receive some form of systemic therapy. Models of logarithmic cell kill indicate that this will be more effective when directed at smaller micrometastatic foci. Potential risks and morbidity have hitherto restricted use of chemotherapy among lymph node-negative patients, and the data cited therein do not appear prima facie to justify expansion of current recommendations to tumors of 1 cm or less. Identification of those patients with micrometastatic disease will help rationalize systemic therapy, but absolute gains may remain modest and selection criteria imperfect. Nonetheless, some patients may be denied the chance of elimination of micrometastatic disease if systemic therapy is withheld at the time of presentation. Detection of occult bone marrow metastases may represent a promising method for identifying patients who will relapse and hence benefit most in absolute terms from systemic chemotherapy. A clinical trial to investigate the prognostic significance of bone marrow micrometastases in patients with T1 lymph node-negative tumors would be useful; limited data suggest that up to 85% of patients with occult micrometastases eventually relapse (4).