Does tumor size trump biology

The widespread use of screening technologies has resulted in the identification of tumors that are significantly smaller in size. This has resulted in thought-provoking issues related to systemic therapy, especially chemotherapy, for these patients. In early days of chemotherapy, tumors > 2 cm were considered high risk and merited the use of adjuvant chemotherapy. More recently, in the 1990s, when taxanes were introduced, the trials were open for patients with node-positive or high-risk node-negative breast cancer. The definition of high risk was > 1 cm irrespective of estrogen receptor (ER) status. The decisions with regard to size and biology were also made easier by the fact that there is a good correlation between tumor size and grade; larger tumors are generally of high grade. As we understand more and more about tumor biology and as the tumor sizes continue to plummet, the question of relative importance of these distinct parameters of assessing tumors has come to the forefront. In this issue of the Clinical Breast Cancer, Chereau et al present the data with regard to the outcomes of breast cancers detected by magnetic resonance imaging (MRI) screening in patients with BRCA1 or BRCA2 mutations.1 They compare the outcomes with a similar group of patients diagnosed by more traditional means. As one might expect, they find that patients diagnosed through the use of MRI had smaller tumors. However, this did not translate into significant differences in 3-year disease-free or overall survival. They state that the treatment decisions were made as per the St. Gallen guidelines.2 For patients hormone receptor (HR)–negative or high-histologic-grade tumors with node-negative disease, these guidelines recommend the use of chemotherapy only if the tumors are > 1 cm. Because significant numbers of the patients with BRCA mutations have high-grade HR-negative tumors but were under 1 cm in size, these patients did not get adjuvant chemotherapy. In fact, patients in the group diagnosed through MRI were half as likely to receive adjuvant chemotherapy (43% vs. 86%). Several studies have analyzed the issue of prognosis in T1ab N0 breast cancers. Leitner et al analyzed a series of 218 patients and found that poor nuclear grade and presence of lymphatic invasion identified a small subset of patients with significant risk of recurrence that warranted adjuvant systemic therapy.3 Studies from the Finland and British Columbia Cancer registries have documented recurrence rates between 15% and 30% for these small tumors.4,5 More recently, there have been back-to-back articles on the outcomes in small HER2-positive tumors, irrespective of their ER status.6-8 These show that HER2 positivity is associated with a twoto five-fold increase in the absolute risks of recurrence. In addition, there is some evidence to suggest that these patients are as likely to benefit from anti-HER2 therapies as those patients with larger tumors.9 There is a dearth of studies analyzing the prognosis of small tumors in the triple-negative population. Evans et al, in a study of 1944 women with screen-detected tumors < 15 mm, showed that basal phenotype was significantly associated with poor survival.10 In addition, there are several aspects of triple-negative tumors that are unique. Size does not appear to be a reliable prognostic factor in these tumors.11 These tumors tend to spread via the hematogenous route rather than by classical lymphatic route12; thus, the tumors are more likely to be understaged. All of these articles bring home a simple message: ignore biology at your peril. So the next question that needs to be answered is how low does one go? The past often provides clues about the future. Since the early 1970s, evaluation of HR status, in addition to size, is routinely performed in the management of invasive cancers. The St. Gallen guidelines recommend the use of chemotherapy for patients with ER-positive tumors only for large (≥ T2) tumors.2 Perhaps the treatment algorithm for the treatment of small (T1ab N0) tumors might be similar to that used in the management of ductal carcinoma in situ, where multiple parameters are used to guide therapy. It is quite possible that a multi-parametric equation that takes into account the patient parameters such as age and menopausal status; tumor characteristics such as histology, immunophenotype, and size; as well as type of surgery and width of margins will enable educated decision making for these small tumors. Based on the recent data in ER-positive tumors,13 one may also postulate that race could play a role in determining outcome. Needless to say, women need to be made aware of the risks and benefits of therapies and be involved in the treatment of their cancer.