Survival From First Recurrence: Relative Importance of Prognostic

Factors in 1,015 Breast Cancer Patients

By Gary M. Clark, George W. Sledge, Jr, C. Kent Osborne, and William L. McGuire
Univariate and multivariate analyses of potential
prognostic factors for 1,015 women with recurrent
breast cancer confirmed that the site of initial recurrence is an important determinant for predicting survival from the time of initial recurrence. However,
both estrogen receptor (ER) status and axillary lymph
node status at diagnosis, as well as the length of the
disease-free interval, provide additional independent
information for predicting patient survival after disease recurrence. Involved axillary lymph nodes at the
time of initial diagnosis and/or lack of ERs may indi-

PATIENTS

WITH recurrent breast cancer

usually die of their disease. However, the
clinical course of women with metastatic breast
cancer is highly variable. Some patients undergo
explosive growth while others have a more gradual progression. Numerous investigators have
examined potential prognostic factors for predicting time to recurrence for patients with primary disease or response to therapy for patients
with advanced disease. Less attention has been
paid to evaluating prognostic factors for predicting survival from the time of first relapse.
Several investigators have shown that the
course of recurrent breast cancer is related to the
site of metastasis. 1-8 Recurrences in soft tissue,
bone, and viscera have been associated with progressively worse survival, respectively.
Estrogen receptor (ER) status has been correlated with disease-free interval and survival after
primary surgery, tumor histology, tumor cell kinetics, degree of aneuploidy, and response to

cate a highly malignant tumor or a weak host defense, either of which might be related to short survival after relapse. Patients with ER-negative tumors
recurred more often in visceral and soft-tissue sites,
while patients with ER-positive tumors were more
likely to recur in bony sites. However, for each metastatic site, receptor-positive patients had longer survival than receptor-negative patients.
J Clin Oncol 5:55-61. @ 1987 by American Society of
ClinicalOncology.

Other factors that have been investigated for

correlation with patient survival after disease recurrence include the stage of disease and size of
the primary tumor at the time of diagnosis,5'14-1

the length of the disease-free interval, 1""9 and

adjuvant treatments. 20 Most of these studies have
analyzed factors one at a time without taking into
account the effects of other variables. For example, ER + patients appear to have longer survival
than ER - patients. But could this be due to
longer disease-free intervals associated with ER
positivity rather than ER itself?
We analyzed data from a group of 1,015 women with recurrent breast cancer in order to examine combinations of potential prognostic factors
available at the time of first recurrence. By taking into account the interrelationships between
these potential prognostic factors, a better predictive index for survival of patients with recurrent disease might emerge.

hormonal therapy. -11The picture emerging from

steroid receptor studies is one in which tumors

lacking estrogen receptors (ER -) are histologically and kinetically more aggressive. Patients
with ER - tumors have shorter disease-free intervals after surgery and poorer survival than patients with tumors that are ER-positive (ER +).
Relationships have also been observed between
8 "2-14 RecurER status and sites of recurrence. 4,6-,
rences among ER - patients tend to be in visceral sites, whereas ER + patients are more likely to
recur in the bone.

From the Department of Medicine/Oncology, University of

Texas Health Science Centerat San Antonio and the Divisionof
Hematology/Oncology, VA Medical Centerat IndianaUniversity, Indianapolis
Submitted December 18, 1985; accepted August 14, 1986.
Supported by National Institutes of Health Grant No. CA
30195.
Address reprintrequests to Gary M. Clark, PhD, Department
ofMedicine/Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX
78284.
1987 by American Society of Clinical Oncology.
0732-183X/87/0501-0003$3.00/0

Journal of Clinical Oncology, Vol 5, No 1 (January), 1987: pp 55-61

55

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Copyright 1987 American Society
of Clinical Oncology. All rights reserved.
138.253.4.233

CLARK ET AL

56
MATERIALS AND METHODS
Patients
Patients were identified retrospectively from a large database
of patients who had ER assays performed in our laboratory
between 1971 and 1983. Patients who met the following criteria
were selected for this study: (1) presentation with disease that
was confined to the breast or regional lymph nodes, (2) radical
or modified radical mastectomy, (3) an interpretable ER assay at
the time of diagnosis, (4) subsequent recurrence, and (4) identification of the site(s) of initial recurrences. Patients were diagnosed, treated, and observed by several physicians at different
hospitals, but all steroid receptor assays were performed in a
single laboratory (W.L.M.).
Recurrences were classified as visceral (brain, liver, lung, or
other sites), bone, soft tissue, or contralateral breast. Sites of
recurrence were documented by physical exam, x-rays, and/or
scans. More than one third of the patients had initial recurrences
in more than one site. Certain analyses were performed using the
specific sites of recurrence, whereas others required that patients
be categorized into distinct types of recurrences. For the latter
analyses, a hierarchy of recurrences with progressively worse
prognosis was assumed to be contralateral breast, soft tissue,
bone, and viscera. Patients were classified into the worst category when more than one site of recurrence was recorded.

Potential Prognostic Factors

ER was measured by the dextran-coated charcoal method as
previously described. 21Tumors with at least 3 fmol/mg cytosol
protein of ER were defined to be ER +. Since relatively few
patients had subsequent ER assays performed at the time of
recurrence, the ER value at the time of diagnosis was used for all
patients. Other variables analyzed included the number of positive axillary lymph nodes at diagnosis, the size of the primary
tumor at diagnosis, menopausal status and age at recurrence,
type of adjuvant therapy (if any), disease-free interval, and the
number and type of initial recurrences.

basis. Data was abstracted from patient charts and clinic records.
Because the collaborative relationships have been in existence
for several years, most of the physicians recorded the information in a standardized format for easy abstraction and
verification
All data collected was entered into a computerized database
and verified to eliminate data entry errors. Results of each visit
or submission of forms were returned to the collaborating physician for additional quality control.

Statistical Analyses
The variable of interest was survival measured from the time
of first recurrence. Univariate survival distributions were estimated using the method of Kaplan and Meier2 2 and compared
using the log rank test. 23 Potential prognostic factors were analyzed m a multivariate analysis using Cox's partially nonparametric proportional hazards model. 24 Because of the large sample size, all tests were performed at the 0.01 level of
significance. All analyses were performed using BMDP statisti25
cal software.

RESULTS
Between 1971 and 1983, 4,271 women with
primary breast cancer had ER assays performed
in our laboratory on a specimen from their primary tumor. A total of 1,122 of these women were
known to have subsequently recurred. Complete
information about the site(s) of initial recurrence
was available for 1,015 of these patients, who
form the basis of this study.
Demographic characteristics of this study
group are presented in Table 1. Sixty-two percent of the patients had positive axillary nodes,
Table 1.

Data Collection
Patients included in these analyses were selected from a large
database of patients who have had steroid receptor assays performed in a single laboratory. When the tumor specimen is sent
to the laboratory, it is accompanied by a standardized form that
includes the names of the patients, the surgeon, and the referring
physician; the hospital, surgery, and pathology identification
numbers; and demographic information about the patient.
For patients outside the south Texas area, a data collection
form was sent to the collaboratmg physician. This form was
designed to capture information about the history, diagnosis.
and treatment of the breast cancer. Follow-up forms requesting
information about recurrence and survival status were sent on an
annual basis. In the event the patient has recurred or therapy has
been changed, several additional data items were requested. The
most notable items were the sites of recurrence and the therapy
that was administered. Fifty-four percent of the study patients
were from outside south Texas.
For patients in the south Texas area, a team of experienced
data managers visited each physician's office or clinic to obtain
these same data items. Each medical oncologist was visited on a
quarterly basis, and each surgeon was visited on a semi-annual

Demographic Characteristics

Variable
No. of positive nodes
0
1-3
> 3
Size of primary tumor

- 2 cm
2-5 cm
> 5 cm
Unknown
ER level
- 3 fmol/mg (ER+)
< 3 fmol/mg (ER-)
Menopausal status at relapse
Post
Pre
Indeterminant
Disease-free interval
Median, 22 months; range, 1-110
Age at relapse
Median, 58 years; range, 25-88

N (%)
377 (37)
214 (21)
424 (42)

309 (33)
463 (50)
164 (17)
79
682 (67)
333 (33)
776 (82)
167 (18)
72

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138.253.4.233

57

PROGNOSTIC FACTORS FOR BREAST CANCER

and 67% had primary tumors larger than 2 cm in
diameter. Two thirds of the patients were ER + .
Most patients were postmenopausal, and the median age at first recurrence was 58 years, (range,
25 to 88 years). The median disease-free interval
was 22 months, (range, 1 to 110 months).
The type of adjuvant therapy administered to
this group of patients is shown in Table 2. More
than one third of patients received no adjuvant
therapy. Twenty-seven percent received postoperative radiation therapy, alone or with another
modality. Less than one third received adjuvant
chemotherapy, either alone or with another modality. Chemotherapy regimens included cyclophosphamide, methotrexate, 5-fluorouracil
(CMF) or CMF-like regimens (62%); phenylalanine mustard, plus or minus 5-fluorouracil
(18%); doxorubicin-containing regimens (8%);
and miscellaneous treatment (12%).
Thirty-eight percent of all patients had initial
recurrences in visceral sites. Approximately one
half of these patients had simultaneous recurrences in bony or soft-tissue sites. The frequencies of recurrences predominantly in bone, soft
tissue, or contralateral breast were 27%, 28%,
and 7%, respectively. The specific sites of initial
recurrence are displayed in Table 3. ER - patients had significantly more recurrences at each
of the visceral sites and the soft-tissue sites than
ER + patients. ER + patients were more likely
to recur in bony sites. A higher proportion of
ER - patients recurred in multiple sites (44%)
than did ER + patients (31%).
A total of 629 of these patients (62%) had died
at the time of this analysis. The median followup past the first recurrence for those patients still
alive was 20 months (range, 1 to 105 months).
Table 2.

Adjuvant Therapy

Therapy
None
Chemotherapy only
Radiotherapy only
Endocrine therapy only
Chemotherapy and radiotherapy
Radiotherapy and endocrine therapy
Chemotherapy and endocrine therapy
Chemotherapy, endocrine therapy, and
radiotherapy

No. of
Patients
(%)
389
174
151
140
69
39
37

(38)
(17)
(15)
(14)
(7)
(4)
(4)

16 (2)
1,015

Table 3.

Sites of Recurrence by ER Status

Site
Brain
Liver
Lung
Other viscera
Bone
Soft tissue
Contralateral breast
Multiple sites

ER- *
ER+
(N= 333) (N= 682)
9%
17%
28%
9%
33%
51%
6%
44%

5%
10%
15%
9%
44%
41%
12%
31%

P Valuet
.0025
.0007
.0001
.98
.0008
.0036
.0071
.001

*ER - < 3 fmol/mg cytosol protein.

tP value by chi square test.

The median survival from first relapse was 23

months.
The results of analyzing the potential prognostic factors one at a time are presented in Table 4.
Specific sites of recurrence and the number of
metastatic sites, ER status and axillary lymph
node status at diagnosis, the size of the primary
tumor at diagnosis, adjuvant chemotherapy and
radiotherapy, and disease-free interval were significantly associated with survival from first recurrence. Age and menopausal status at relapse,
adjuvant endocrine therapy, and soft-tissue recurrences were not significant predictors of survival. Patients with contralateral breast recurrence had significantly longer survival than
patients who recurred in other sites. This is probably because the majority of these patients had
second breast primaries rather than recurrent disease and may have been rendered disease-free by
the time of their second surgery. The relationship
between recurrence site and survival are shown
separately for ER + and ER - patients in Figs
1A and IB, respectively. For both groups, patients with visceral disease had a significantly
worse prognosis than patients with bony disease,
and patients who recurred in bony sites had significantly shorter survival than patients with softtissue recurrences. When ER status was examined by site of recurrence (Fig 2), ER + patients
had longer survival than ER - patients, no matter what the site of recurrence.
Table 5 shows the results of analyzing the potential prognostic factors in a multivariate manner. It must be noted that in order to perform a
multivariate analysis, it is necessary that information be available on every potential prognostic
factor examined in the model. Since information

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58

CLARK ET AL
Table 4.

Univariate Survival Analyses

Variable
No. of positive nodes
0
1-3
>3
Size of primary tumor
S2 cm
2-5 cm
> 5 cm
ER level
-- 3 fmol/mg (ER +)
< 3 fmol/mg (ER -)
Adjuvant chemotherapy
No
Yes
Adjuvant endocrine therapy
No
Yes
Adjuvant radiotherapy
No
Yes
Disease-free interval
S60 mo
24-60 mo
12-24 mo
< 12 mo
Age at relapse
- 50 yr
< 50 yr
Menopausal status at relapse
Post
Pre
No. of recurrence sites
>1
> 1
Brain recurrence
No
Yes
Liver recurrence
No
Yes
Lung recurrence
No
Yes
Bone recurrence
No
Yes
Soft-tissue recurrence
No
Yes
Contralateral breast recurrence
No
Yes

Median
Survivalt
P Value*
(mo)
<.0001

377
214
424

30
26
16
<.0001

309
463
164

29
21
14

was not available for at least one of these factors

for 114 patients, the sample size was reduced to
901 for this analysis. Visceral and bony recurrences, ER status and axillary lymph node status
at diagnosis, and disease-free interval continued
to correlate significantly with patient survival,
but tumor size, adjuvant therapy, and the number
of metastatic sites were no longer significant predictors of survival. Neither age nor menopausal
status at relapse entered the model.
DISCUSSION

<.0001

28

682
333

26
17

well known risk factors for early recurrences are,

24

therefore, overrepresented. For example, more

<.0001
719
296
.13
783
232

19

patients had positive axillary lymph nodes and

24

pect in the general breast cancer population. 26

Our analysis of 1,015 relapsed patients demonstrated that there are several independent prog-

.0015
740
275

18
<.0001

35

80
364
309
262

nostic factors for predicting survival from the

19

time of initial recurrence. Site of recurrence, ER

.09

23
.22

24
24

776
167

large ER - primary tumors than one would ex-

27
16

725
290

The patients included in this study do not rep-

resent a random cross section of patients with

primary breast cancer. They all presented with
primary disease, but subsequently recurred. The

14

status and axillary lymph node status at diagnosis, and the length of the disease-free interval
were significantly associated with survival, both
as single factors as well as in combination.
Because these patients were diagnosed and
treated by physicians at several different hospi-

<.0001
667
348

28
15

1.o
S,
oft T--..

<.0001
941
62

0.8

24
6

o,,

71

<.0001
874
122

25
10

02.

<.0001
805
193

25
14
<.0001

597
404
.08
545
461
<.0001
905
97

*P values by log rank test.

tMedian survival estimated from Kaplan-Meier curves.

0.04
0

Fig 1.

24

48
72
Months

86

120

24

48

72

96

120

Months

Survival after first recurrence by ER status.

Independent of ER status, patients with soft-tissue

recurrences survived longer than patients with bony
recurrences, and patients with bony recurrences survived longer than patients with visceral recurrences.
Median survival for ER + patients (A) was 47, 24, and
16 months for soft tissue, bone, and visceral sites,
respectively (P < .001 for soft tissue v bone; P = .006
for bone v visceral). Median survival for ER - patients
(B) was 25, 16, 10 months, respectively, for soft tissue, bone, visceral sites (P = .007 for soft tissue v
bone; P = .02 for bone v visceral).

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PROGNOSTIC FACTORS FOR BREAST CANCER

59

1.0

NB

o.a
0.6

"I
A.4
'

ER+

0.2
,.ER+
ER-

0.0
U0

48

72

96

120

Months

24

48

72

96

ER120

Months

Multivariate Survival Analysis Using Cox's

Model

Variable
Brain recurrence
Liver recurrence
ER status
No. of positive nodes
Lung recurrence
Disease-free interval
Bone recurrence

48

72

Months

tals, it is likely that different diagnostic procedures were used to document the time and site of
recurrence and that the follow-up may have varied among institutions. Delayed detection of recurrences would artificially shorten the observed
survival time. However, the median survival
times observed in this series of patients are not
shorter than those reported by other investigators,-7 suggesting that this potential bias is minimal in this series of patients.
Previous investigators have suggested a relationship between ER status and sites of recurrence. Singhakowinta et all 2 found that ER+
tumors were more likely to recur in bone, and
ER - tumors in viscera. Although steroid receptor assays in that study were performed mostly on
metastatic tumors, subsequent studies on primary tumors have supported the earlier conclusions. 4 6-8 In our series also, ER + tumors were
more likely to recur initially in bone than ER tumors, whereas ER - tumors recurred more often in visceral or soft-tissue sites.
Our findings differ from those of previous investigators in a number of ways. Most studies 4'8'12have been unable to discern any differences in ER status regarding soft-tissue
Table 5.

Coefficient

SE

P Value

+ 1.1745
+0.8228
-0.6238
+0.3208
+0.4131
-0.0093
+0.2997

0.1565
0.1181
0.0906
0.0503
0.1015
0.0025
0.0871

<.0001
<.0001
<.0001
<.0001
<.0001
.0002
.0006

NOTE. Positive coefficients indicate that presence of that

factor correlates with decreased survival. ER negativity and
short disease-free intervals also correlates with decreased survival.

120

Fig 2. Survival after first recurrence by site of relapse. ER+

patients had longer survival than
ER - patients regardless of initial
site of recurrence (P<.001). Median survival times were 47 and 25
months for soft tissue sites (A), 24
and 16 months for bony sites (B),
and 16 and 10 months for visceral
sites (C).

recurrence, although Lee and Markland' 3 found

that recurring lesions of patients who had high
ER levels were much more likely to be of soft
tissue only. In our study, when recurrences in the
opposite breast were combined with local-regional recurrences into the soft-tissue category,
ER - and ER + patients had approximately the
same recurrence rates. However, recurrences in
the contralateral breast were twice as prevalent
(12% v 6%) in ER + patients. Thus, their inclusion in a soft-tissue category might counterbalance the general ER negativity of chest wall and
ipsilateral lymph node recurrences.
Few studies have subdivided the visceral metastases by organ site; those who did found ER patients more likely to recur initially in the brain
and liver, but not in the lung.4 ,7 However, the
sample sizes in these studies were relatively
small. In our series, ER - patients were more
likely than ER + patients to recur in all visceral
sites, including the lung.
The median survival from first recurrence for
the entire group was 23 months. However, survival was greatly influenced by the site of initial
recurrence, ER status and axillary nodal status at
diagnosis, and disease-free interval. Each of
these factors has been identified by other investigators, but they have not been analyzed together
in a multivariate manner.
Within a metastatic site, ER status affects survival. Not only are patients with initial bony recurrences more likely to have ER + tumors, but
if their tumors are ER +, they will live longer
than patients with ER - bone recurrences. Similarly, not only are initial visceral recurrences
more commonly ER-, but ER - tumors in visceral sites are associated with poorer survival
than ER + visceral metastases. ER - patients
with visceral recurrences have a dismal 10month median survival from time of recurrence,

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138.253.4.233

60

as opposed to 16 months for ER + patients.

These results extend the previous observations
suggesting the generally better prognosis for
ER + tumors.
It is possible that ER status at the time of
recurrence may differ from the ER status at diagnosis,2 7 and that changes in receptor status may
be of prognostic significance. Gross et a128 have
shown that loss of progesterone receptors is associated with decreased survival. However, recurrences do not always occur in easily biopsiable
locations, and even when they did, ER status was
not routinely reassessed in this patient population. One might postulate that ER status at recurrence might be a better prognostic indicator for
patient survival past the time of relapse.
Tumor stage of axillary nodal status at diagnosis has been investigated as a prognostic factor at
the time of first recurrence. Howell et all'4 found
that axillary node status and tumor size were
predictors of recurrence, but neither influenced
15
the length of survival after relapse. Devitt ,16
found that patients with locally confined disease
at diagnosis had longer disease-free intervals and
survived longer than patients with more advanced disease. However, it is possible that the
relationship observed between stage and survival
might have been due to the increased disease-free
interval, ER status, or other prognostic factors.
Pater et a15 examined stage, tumor size, pathologic status of nodes, and disease-free interval in
multivariate analyses and found that the stage of
disease was related to survival even after adjusting for the disease-free interval. However, ER
status was not available for these patients. In our
study, axillary nodal status continued to be a
strong prognostic factor for survival from initial
recurrence after adjusting for the site of recurrence, ER status, and disease-free interval. Involved axillary lymph nodes may indicate a highly malignant tumor and/or weak host defense,
either of which might be related to short survival
after relapse.
It is of interest to speculate on the relationship
between adjuvant chemotherapy or postoperative
radiation and survival. Both were associated
with significantly shorter survival after recurrence. Although administration of adjuvant therapy appeared to be an important factor when
analyzed in a univariate manner, all statistical
significance disappeared in the multivariate anal-

CLARK ET AL

yses. This is probably because the decision to

administer adjuvant therapy was based on factors
such as nodal status and ER status, and the effectiveness of the adjuvant therapy was related to
the disease-free interval. Once these other factors were taken into account, administration of
adjuvant therapy provided little additional information regarding patient survival. The decreased
survival for the patients receiving adjuvant therapy may also be related to the inability to administer more aggressive treatment at the time of
recurrence.
Therapy following recurrence was not incorporated into the statistical models. The treatments that these patients received were not
uniform with respect to dosage, timing, or combination with other agents. However, given the
rather dismal treatment results for metastatic
breast cancer, it is doubtful whether different
treatment strategies would have had a major impact on the results of these analyses." A question
of interest, however, is whether the longer survival of ER + patients could be explained by the
fact that these patients are more likely to respond
to endocrine therapy. In an attempt to address
this question, we analyzed the subset of patients
who received no endocrine therapies after relapse (N = 343). As one might expect, the majority of these patients (N = 181) were ER - and
were not candidates for endocrine therapies.
Among the 162 ER + patients, 41 had borderline
values (3 to 10 fmol/mg protein). Fifty-one of the
121 patients with ER values > 10 fmol/mg received chemotherapy. The majority of the remaining ER + patients either had aggressive, extensively visceral disease, or recurrences in the
contralateral breast, which resulted in a second
mastectomy. Even in this subgroup, the ER +
patients had significantly (P < .0001) longer
survival than the ER - patients (median survival, 24 months v 12 months, respectively).
In conclusion, we have confirmed that the site
of initial recurrence is an important prognostic
factor for predicting survival from the time of
initial recurrence. However, based on multivariate analyses, both ER status and axillary lymph
node status at diagnosis, as well as the length of
the disease-free interval, provide additional independent information for predicting patient survival. Several recent studies had demonstrated
that progesterone receptor status is another im-

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138.253.4.233

61

PROGNOSTIC FACTORS FOR BREAST CANCER

portant prognostic factor that may be even more

powerful than ER status for certain subsets of
patients. Since the methodology for routinely
measuring this receptor was only developed in
the mid-1970s, these values were not available
for many of the patients in this series. It will be of
interest to see how progesterone receptor status
combined with other prognostic factors influences survival after relapse.

ACKNOWLEDGMENT
We are indebted to Judy Wenzel and Nancy Pullin for data
collection and data management and to the many physicians who
provided tissue samples for the steroid receptor assays and follow-up information about the patients: Drs C. A. Hubay, O. H.
Pearson, J. S. Marshall, Case Western Research Hospital,
Cleveland; Dr A. Carter, Downstate Medical Center, New
York; and Dr A. Segaloff, Ochsner Medical Center, New Orleans.

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