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Purpose: This analysis was performed to clarify the associated with a worse prognosis (including grade 3
relationship of young age at diagnosis to the pathologic histology, lymphatic vessel invasion [LVI], necrosis, and
features of the tumor and prognosis in patients with estrogen receptor [ER] negativity) as compared with
early-stage breast cancer. older patients. In a proportional hazards model that in-
Patients and Methods: We retrospectively analyzed cluded clinical and treatment-related variables, as well
data from 1,398 patients with American Joint Committee as these pathologic features, age younger than 35 years
on Cancer Staging stage I or II breast cancer treated by remained a significant predictor for time to recurrence
breast-conserving therapy between 1968 and 1985. (relative risk [RR], 1.70), time to distant failure (RR, 1.60),
One hundred seven patients were younger than 35 years and overall mortality (RR, 1.50).
at the time of diagnosis. The median follow-up duration Conclusion: Breast cancer patients younger than 35
for the 1,032 survivors was 99 months. years have a worse prognosis than older patients. This
Results: Patients younger than 35 years had a sig- difference is only partially explained by a higher fre-
nif-fcanty higher overall recurrence rate (P = .002), as quency of adverse pathologic factors seen in younger
well as a greater risk for developing distant metastases patients.
(P = .03), when compared with older patients. The can- J Clin Oncol 12:888-894. 1994 by American So-
cers in younger patients more commonly showed factors ciety of Clinical Oncology.
Table 1. Prevalence of Patient Characteristics and Pathologic Features (grade 3 histology, EIC, LVI, necrosis, and MCR) to
Stratified by Age Group
decrease with increasing age.
Age (years)
Characteristic < 35 35-50 51-65 > 65 P. Univariate Relationship Between Age and Treatment
Total no. of patients 107 576 450 265
Outcome
No. with pathology 103 474 356 202 Patients aged younger than 35 years had a greater prob-
%with pathology 96 82 80 76
ability of recurrence at all time periods (Fig 1A; P =
%T1 57 58 57 52 NS
% size > 3 cm 13 15 15 18 NS .002). At 5 years, the actuarial recurrence rate for patients
% nodes positivet 32 37 37 40 NS younger than 35 years was 36% as compared with 24%
% > 3 nodes positive 5 9 10 7 NS for patients aged 35 to 65. This difference persisted at 10
% ER positive 26 50 66 81 < .001 years, at which time the actuarial recurrence rates were
% node dissection 93 95 73 36 < .001
51% and 37%, respectively. Patients aged younger than
Median volume resected (cc) 34 43 51 48 .04
% receiving chemotherapy 31 35 22 5 < .001 35 years also had an increased risk of distant failure (P
Median dose to breast (Gy) 66.1 66.0 66.0 65.0 .05 = .03), as shown in Fig lB. The 5-year actuarial distant
"%grade 3 47 50 38 24 < .001 failure rate was 24% for patients younger than 35 years
"%EIC-positive 23 24 19 13 .002 as compared with 17% for patients aged 35 to 65. At 10
"%LVI-positive 36 33 23 23 < .001
years, the actuarial rates of distant failure were 37% and
"%necrosis 30 25 21 14 < .001
"%MCR-positive 31 23 15 8 < .001 28%, respectively. Survival among younger patients was
2 also worse (Fig IC). The 5-year actuarial survival rate
*X test for trend; Kruskall-Wallis test was used for comparison of medi-
ans. was 83% for patients younger than 35 years as compared
"tAmongall with information available. with 88% for patients aged 35 to 65; however, this differ-
ence was not statistically significant (P = .11).
Separate comparisons of time to failure for younger
of pathology slides for review and the availability of results for ER
status. In addition to examining models that included all of the
versus older patients, which included patients older than
potential predictors, we performed stepwise analysis to create a final 65 years in the older group, yielded similar results for
model containing only the significant predictors of the outcome in both overall and distant failure. At 5 years, for example,
question. Additionally, we performed stepwise analysis limited to the actuarial recurrence rate was 24% for all patients -
node-positive patients and node-negative patients. 35 years, and the actuarial distant metastasis rate for this
group was 18%. For both analyses, the curves remained
RESULTS
significantly different (log-rank test, P = .001 for all
Patient Characteristicsand Pathologic Features recurrences and P = .048 for distant recurrences). For
The characteristics of patients younger than 35 years the analysis of survival, we excluded patients older than
were similar to those of patients in the three older age 65 years to minimize the competing risks of noncancer
groups with regard to tumor stage, tumor size, and nodal mortality. In patients aged ! 65 years, for example, only
status (Table 1). Patients aged 50 years or younger were 14% of deaths were due to causes other than breast can-
more likely to undergo axillary lymph node dissection cer; however this increased to 49% in patients older than
and were more likely to be treated with adjuvant chemo- 65.
therapy. The higher proportion of women aged 50 years
or younger who received chemotherapy reflected the Multivariate Relationship Between Age and Treatment
treatment philosophy of this period, in which almost all Outcome
node-positive women younger than 50 were treated with To determine if either the variations in treatment or
adjuvant chemotherapy. Younger patients were also more the differences in the prevalence of pathologic features
likely to have a smaller volume of breast tissue resected accounted for the difference in outcome between age
(median volume, 34 cm 3 in patients < 35 years as v 43.3, groups, we performed several multivariate analyses using
51.4, and 48.2 cm3 , respectively, in the three older age the Cox proportional hazards regression model to explore
groups). Additionally, patients in the oldest age group these relationships with regard to time to recurrence, time
received, on average, 1 Gy less to the tumor bed than did to distant failure, and overall survival. Age younger than
the other patients. Younger patients were significantly 35 years remained a significant predictor of recurrence
less likely to have an ER-positive tumor. (relative risk [RR], 1.71; 95% confidence interval [CI],
Comparison of the prevalence of pathologic features 1.27 to 2.30) when entered into a model containing all
by age group (Table 1) showed a highly statistically sig- potential patient, treatment, and pathology variables. Fur-
nificant trend for the prevalence of each feature examined thermore, young age remained a significant predictor of
LAJ LW -. )(83%)
-1 80 B
(72%)
(76%)
'4Z 60 (63%)
h
LQ --- 35-65years
40
(LC
-Sh
- <35years
m
20
k. B
I t
o 5 0 5 10
YEARS YEARS
AT RISK AT RISK
<35 Years 107 67 21 <35 Years: 107 79 25
35-65 Years 1026 731 198 35-65 Years: 1026 797 229
80 - "-8--.. (75%)
(83%)
(71%)
60
Fig 1. (A) Kaplan-Meier analysis showing freedom from recur-
rence related to age group. Patients younger than 35 had a signifi-
cantly worse outcome than did patients aged 35 to 65 (P = .002). (B) 40 ---- 35-65 years
Kaplan-Meier analysis showing freedom from distant failure related - <35years
to age group. Patients younger than 35 had a significantly worse
outcome than did patients aged 35 to 65 (P = .03). (C) Kaplan-Meier
analysis showing overall survival related to age group. The curves 20
are not significantly different (P = .11).
C
O 5 10
YEARS
AT RISK
<35 Years : 107 87 28
35-65 Years: t026 859 243
recurrence, with an RR of 1.70 (P < .001), using stepwise stepwise model containing only significant predictors (Ta-
selection to create a final model containing only signifi- ble 2). In this model, patient age younger than 35 years
cant predictors of this outcome. Age younger than 35 was associated with an increased RR for distant recur-
years also remained a significant predictor of recurrence, rence of 1.60 (P = .009) as compared with patients 35
both in a model limited to patients with positive lymph to 65 years. Also included in the final model were the
nodes (RR, 1.73; 95% CI, 1.05 to 2.84) and in a model presence of more than three positive lymph nodes (RR,
limited to patients without lymph node involvement (RR, 2.38; P < .001), LVI (RR, 1.68; P < .001), histologic
1.69; 95% CI, 1.18 to 2.43). grade 3 (RR, 1.67; P < .001), and the presence of moder-
An examination of predictors specific for time to dis- ate or marked necrosis (RR, 1.38; P = .04). The presence
tant recurrence also included patient age younger than 35 of a moderate or marked MCR (RR, 0.47; P < .001), an
years as a significant risk factor (RR, 1.60; 95% CI, 1.12 EIC (RR, 0.70; P = .02), and tumor size 5 2 cm (RR,
to 2.29) in a complete model containing all possible vari- 0.68; P = .002) was associated with a better prognosis.
ables. Furthermore, young age was included in a final Separate analyses limited to node-negative and node-pos-
Table 2. Significant Predictors of Time to Distant Failure Based on Several groups have previously reported a worse prog-
Proportional Hazards Model nosis for young patients with breast cancer in large popula-
Variable RR 95% CI tion-based studies. Host and Lund2 calculated relative sur-
> 3 nodes positive 2.38 1.72-3.30 vival rates among 31,594 breast cancer patients entered
LVI-positive 1.68 1.31-2.15 into the Norwegian Cancer Registry between 1955 and
Grade 3 1.67 1.26-2.20
1980 and found that relative survival was worse among
Age < 35 years 1.60 1.13-2.27
1.02-1.87
patients aged 34 years or younger and among patients aged
Necrosis 1.38
EIC-positive 0.70 0.51-0.95 75 or older as compared with patients in the middle age
Size - 2 cm 0.68 0.54-0.87 groups. This age effect remained when patients were stra-
MCR-positive 0.47 0.33-0.66 tified by tumor stage, although the difference was more
pronounced in patients with stage II disease. Similarly,
Adami et al' analyzed the relationship between age and
itive patients yielded similar estimates of increased risk relative survival for 57,068 women entered into the Swed-
for both groups (RR, 1.51 v 1.70; 95% CI, 0.96 to 2.38 ish National Cancer Registry between 1960 and 1978.
v 0.99 to 2.93, respectively); however, the smaller number They found that relative survival improved continuously
of events in each group led to wider confidence intervals, with age up to 50 years and declined with increasing age
and thus these results were of only borderline statistical after this point. However, neither study included patients
significance. In addition, young age was associated with who were uniformly staged or treated. Furthermore, neither
an increased risk of death (RR, 1.50; 95% CI, 1.02-2.21) study was able to assess and control for possible differ-
in a model containing all possible predictors. A final step- ences in the pathologic features of the cancer among the
wise model of overall mortality among patients younger different age groups, leaving unclear whether the differ-
than 65 years further showed young age to be a significant ences in survival were due to a different distribution of
predictor, with an RR of 1.50 (P = .04). pathologic features in younger women.
We and others have also previously reported that pa-
DISCUSSION tients younger than 35 years have a greater risk of local
24
Our results show that young breast cancer patients (age recurrence. 1 7- In general, younger patients have an in-
< 35 years) have a worse prognosis than older patients creased rate of local or locoregional recurrence after treat-
in terms of overall recurrence, distant recurrence, and ment with either mastectomy or breast-conserving therapy,
overall survival. Additionally, young patients have a dif- with local recurrence rates nearly doubled in the youngest
ferent distribution of pathologic features, with an in- age groups. Perhaps of greater importance is information
creased incidence of several features that have previously regarding the influence of young age on the risk of distant
been shown to predict for treatment failure. However, in failure and survival. A previous analysis of a much smaller
this series of patients, the increased rate of treatment cohort of patients from our institution" identified several
failure was not entirely explained by these pathologic histologic variables associated with an increased risk of
features. Specifically, even after controlling for this dif- distant failure, but contained too few patients to evaluate
ferent distribution of histologic features, young age re- the effect of age. However, a recent report of the experi-
mained a significant predictor of recurrence (RR, 1.70), ence at the Institut Curie 26 documented an association be-
distant failure (RR, 1.60), and death (RR, 1.50). tween young age and increased risk of distant failure, as
Although young age was a significant predictor of mor- well as a decreased cancer-specific survival. However, the
tality by multivariate analysis, the univariate analysis was study population was a heterogenous mixture of patients
only of borderline significance (P = .11). In large part, (clinical stage I to III) treated by various means ranging
this is explained by the number of events in this series. from radiation therapy without surgery to mastectomy fol-
Although the number of events allowed a greater than lowed by radiation. Furthermore, many pathologic vari-
80% power to detect a 15% difference between the sur- ables that have been shown to predict for worse outcome
vival curves, there was less than 80% power to detect a were not controlled for in their analysis. A recently pub-
difference smaller than 10%. Furthermore, minor differ- lished update of the experience from National Surgical
ences in the covariates among patient age groups may Adjuvant Breast and Bowel Project protocol B-06 27 has
explain why the proportional hazards analysis showed also suggested that patients younger than 40 years do worse
statistically significant results. For example, in this series regardless of treatment modality. However, this finding
of patients, young women had slightly smaller tumors was limited to patients who had lymph node involvement
and were more often node-negative, although these differ- at the time of presentation, and the effect of age on distant
ences were not statistically significant. failure rates remains unclear.
We found that young breast cancer patients have a tumor stage, tumor size, and nodal status among the dif-
different incidence of various pathologic features of their ferent age groups offers some further argument against
tumors as compared with older patients. Specifically, we such a bias in this cohort.
found a statistically significant trend correlating decreas- The clinical implications of these findings are not cer-
ing patient age with an increasing incidence of LVI, poor tain. Data from the Early Breast Cancer Trialists' Collab-
histologic grade, necrosis, presence of an EIC, and MCR. orative Group suggest that younger premenopausal pa-
Several of these features, including histologic grade, EIC, tients experience a similar degree of benefit when treated
and LVI, appeared to increase for patients aged - 50 with standard-dose adjuvant systemic therapy as do older
years, while others more clearly increased monotonically premenopausal patients.3 6 Whether young age per se
with decreasing age. We also observed a higher propor- should be considered as an indication for any or more
tion of ER-positive tumors as patient age increased. Rosen intensive adjuvant systemic therapy, independently of
et al, 28 Fisher et al,29 and Kurtz et al 30 have previously other factors, will require evaluation within randomized
reported an increase in lymphocytic infiltrate and tumor clinical trials.
grade in younger patients. Fisher et al also noted an in- The explanation for the worse prognosis for young
creased incidence of necrosis for younger patients as com- breast cancer patients is not obvious. It is not known what
pared with older patients. Poor histologic grade, LVI, and combinations of genetic alterations are responsible for the
necrosis have previously been shown, in univariate disease or whether there may be different combinations of
and multivariate analyses, to predict for worse out- alterations in different groups of patients. The increased
come. 31-35 However, our study shows that young age re- incidence of various poor-prognostic pathologic factors
mains a significant predictor of worse outcome (in terms among young patients and their worse prognosis even
of overall recurrence, distant failure, and survival) even when corrected for these pathologic features suggest that
after accounting for a greater proportion of these poor the disease may have a different biologic basis in at least
prognostic pathologic features in patients aged < 35 a portion of young patients. We do not have data on
years. Furthermore, we were unable to identify any spe- patients in this series regarding more recently reported
cific constellation of pathologic features that explained prognostic factors, such as HER-2/neu, p53, angiogen-
the particularly poor prognosis of these patients. esis, etc. It is known that young breast cancer patients
As the patient population for this analysis is a select have a greater likelihood of having an inherited form of
group that included only those patients who received the disease3 7 and a greater annual incidence of developing
treatment at our institution, it is possible that the patients another breast cancer in their opposite breast.3 8 Further
analyzed in this cohort may not be representative of breast research is necessary to establish the genetic alterations
cancer patients as a whole. This group, for example, con- responsible for the disease and whether these are the same
tains a greater proportion of younger patients than would for young and older breast cancer patients. The identifi-
be expected from epidemiologic series. However, during cation of the specific locus on 17q21 associated with
the time period considered, the major determinant for early-onset high-risk breast cancer kindred 37 may be one
choice of local treatment was not tumor histology, but such opportunity to establish the biologic basis of the
rather patient self-selection for breast conservative sur- disease in relation to age at diagnosis.
gery or mastectomy. We are unaware of any systematic
bias by age that would have accounted for a greater pro- ACKNOWLEDGMENT
portion of patients destined to fail to respond to treatment The authors are grateful to Dr Frederick Li for invaluable advice
in the younger age groups. Indeed, the equivalence of and critical comments during preparation of the manuscript.
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