Purpose: Axillary lymph node status is the single most important prognostic
variable in the management of patients with primary breast cancer. yet, it
is not known whether metastasis ta the axillary nodes is simply a time-dep
endent variable or also a marker for a more aggressive tumor phenotype, The
purpose of this study was to determine whether nodal status at initial dia
gnosis predicts outcome after relapse and therefore also serves as a marker
of breast cancer phenotype,
Patients and Methods: Survival experience after first relapse in 1,696 prim
ary breast cancer cases was analyzed using Cox proportional hazards regress
ion. The following explanatory variables and their first-order interactions
were considered: number of axillary lymph nodes involved (zero v one to th
ree v four or more), hormone receptor status (any estrogen receptor [ER] ne
gativity v ER negativity/progesterone receptor positivity v other ER positi
vity), primary tumor size (< 2 cm v 2 to 5 cm v > 5 cm), site of relapse (l
ocoregional v distant), disease-free interval (< 1.5 years v 1,5 to 3 years
v > 3 years), adjuvant endocrine therapy (none v any), adjuvant chemothera
py (none v any), and menopausal status (pre-, peri-, or postmenopausal).
Results: Axillary lymph node status, site of relapse, and hormone receptor
status were all highly significant as main effects in the model. After adju
stment for other variables, disease-free interval alone was only modestly s
ignificant but interacted with nodal status, After disease-free interval, h
ormone receptor status, and site of relapse were accounted for, survival af
ter relapse was poorer in node-positive cases, when compared with node-nega
tive cases. The hazard ratios for patients with one to three and four or mo
re involved nodes were 1.2 (95% confidence interval [CI], 0.8 to 1.9) and 2
.5 (95% CI, 1.8 to 3.4), respectively.
Conclusion: Patients with four or more involved nodes at initial diagnosis
have a significantly worse outcome after relapse than node-negative cases,
regardless of the duration of the disease-free interval. We conclude that n
odal metastasis is not only a marker of diagnosis at a later point in the n
atural history of breast cancer but also a marker of an aggressive phenotyp
e. (C) 1999 by American Society of Clinical Oncology.