(CANCER RESEARCH 48, 7067-7071, December 15, 1988]

A Gompertzian Model of Human Breast Cancer Growth1

Larry Norton2
Department ofNeoplastic Diseases, Mount Sinai Medical Center, New York, New York 10029

N(t) =

ABSTRACT
The pattern of growth of human breast cancer is important theoreti
cally and clinically. Speer et al. (Cancer Res., 44: 4124-41.10, 1984)
have recently proposed that all individual tumors initially grow with
identical Gompertzian parameters, but subsequently develop kinetic het
erogeneity by a random time-dependent process. This concept has elicited
interest because it fits clinical data for the survival of untreated patients,
for the progression of shadows on serial paired mammograms, and for
time-to-relapse following mastectomy. The success of these curve-fits is
compelling, and the model has been applied to clinical trials. However,
the assumption of uniform nascent growth is not supported by theory or
data, and individual cancers have not been shown to follow the complex
growth curves predicted by the Speer model. As an alternative, if kinetic
heterogeneity is understood to be an intrinsic property of neoplasia, the
same three historical data sets are fit well by an unadorned Gompertzian
model which is parsimonious and has many other intuitive and empirical
advantages. The two models differ significantly in such clinical projec
tions as the estimated duration of silent growth prior to diagnosis and
the anticipated optimal chemotherapy schedule postsurgery.

INTRODUCTION
Many models of tumor growth have been proposed to fit
clinical data and to offer therapeutic guidance (1, 2). Each
model is to some extent dependent on the assumption of a
certain pattern of growth of the unperturbed tumor. The land
mark work of Skipper and colleagues, for example, was based
on exponential kinetics (3). In exponential growth the cell
number TVis a function of the starting size N(0), the time of
growth f. and a constant b. by the formula:
N(t)

Hence, the time fd required for N(t\) to double, i.e., N(t\ +

t)/N(t)
= 2, is always constant at loge(2)/.
The Skipper model,
developed principally for experimental murine leukemia, con
tinues to yield valuable insights into the relationship between
tumor size, growth characteristics, and therapeutic response
(4). More recent models have also depended upon the exponen
tial curve. An example is the reconsideration by Goldie and
Goldman (5) of the Delbruck-Luria mutagenesis model (6) as
extended by Law from bacteria to cancer (7).
The exponential pattern of growth can be useful when it fits
actual data, but it is now known not to be universally appropri
ate. In particular, in many types of growth
normal and neoplastic
t,, is not constant, but increases as the population size
increases. To many of these cases Laird (8) successfully applied
Gompertz' equation, originally developed for actuarial analysis,
but later proposed as a growth curve (9). In Gompertzian
growth /V(') is a function of A'(0), t, and h. but also a limiting
size jV(),
by the equation:
Received 12/29/87; revised 8/5/88; accepted 8/1 1/88.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisement in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1Supported in part by the Chemotherapy Foundation, New York, and the T.
J. Marteli Memorial Foundation, New York.
1To whom requests for reprints should be addressed, at Department of
Neoplastic Diseases, Mount Sinai Medical Center, One Gustave L. Levy Place,
P. O. Box 1129, New York, NY 10029.

.[l - exp(-Af)]|

where k = log,[N(>)/N(0)].
This equation fits experimental (10) and clinical data (11),
and uncovers growth-regulatory mechanisms in animal (12, 13)
and human (14) cancers. In addition, when used to relate a
tumor's size to its rate of regression in response to therapy (15),
Gompertz1 equation has aided in the design of successful clinical
trials (16, 17).
Recently, however, the validity of the assumption of Gom
pertzian growth for clinical breast cancer has been challenged
by the provocative new model of Speer et al. (18). These authors
propose a stochastic process in which growth is fundamentally
Gompertzian, but with random, spontaneous alterations in the
parameters such that h decreases and A'()increases in a
functionally related manner. This results in growth "spurts."
They postulate that both b and N(<*>)are constant for all tumors
at inception, and the probability of random change is independ
ent of N(t), i.e., a large tumor has the same chance of undergoing
an alteration as a small tumor. Tumor heterogeneity is a con
sequence of the randomness of the process. This model was
constructed so as to reconcile the Gompertzian parameters
described for multiple myeloma and in vitro breast cancer cells
(19) with "preconceived notions of the timing of the natural
history" of clinical breast cancer. It predicts an average of 8
years of growth from one cell to clinical recognition at 1 x IO9
to 5 x 109 cells. Of greatest interest, the model fits two-point
volume data for early (mammographically discernible) tumors
(20), survival data for untreated cancers (21), and remission
duration data post-mastectomy (22). It suggests that the shorter
time-to-relapse after mastectomy for those patients who had
more axillary nodal involvement is due to a positive linear
relationship between number of involved nodes and number of
metastatic sites. This view of theirs is in contrast to a previously
hypothesized and widely accepted relationship, that patients
with more involved nodes have a greater total-body tumor cell
burden (4). Additionally, the Speer model anticipates merit in
long-term maintenance chemotherapy in the postsurgical ad
juvant setting, as opposed to current short-term, intensive ap
proaches.
The Speer model is theoretically intriguing. The concept of
random spontaneous change in growth rate recalls the powerful
theory of tumor progression (23, 24). The inverse relationship
between b and N(<*>)has indeed been previously described (12).
Nevertheless, curves consistent with the Speer model have not
been fit in individual cases, as has been done innumerable times
for the Gompertzian model. Additionally, the assumption of a
uniform b and N()
for all primary breast cancers at onset of
growth is not consistent with the known biological heteroge
neity of breast cancer on the cellular or even molecular level (2,
25, 26). Indeed, the construction of such complicated curves as
found in the Speer model is made necessary only if a uniform
initial b is hypothesized. If variability in b is allowed, the
unmodified Gompertzian model is sufficient to fit clinical data.
This is shown below by the analysis of the same three data sets
used by Speer.

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BREAST CANCER MODEL

MATERIALS AND METHODS

The first data set used by Speer was provided by Bloom et al. who
collected data for 250 women with untreated breast cancer followed at
the Middlesex Hospital, London, during the period 1805 to 1933 (21).
All patients had confirmation of the histological diagnosis at necropsy.
58% of the women were over the age of 50. The initial symptom for
83% was a breast lump, and for 71% there was a delay between first
symptom and presentation to hospital of more than 1 year. The duration
of life from onset of symptoms to death is graphed as square points in
Fig. \A: median survival is 2.7 years, and fewer than 1% of patients
survived for more than 15 years. These results are similar to earlier
reports (27, 28).
These data are analyzed here as follows: ,\ (/) is an individual patient's
tumor size at a time t measured from the onset of symptoms at time 0.
The tumor size at onset of symptoms is N(Q) and /V()
is held constant.
Parameter b is allowed to vary, which produces a family of Gompertzian
curves which intersect only at A'(O).For the group of 250 patients Pi_(t)
is the proportion of patients who have died by or at time t because their
tumor sizes had reached a lethal tumor size NL at some time less than
or equal to t. By rearrangement of the Gompertz equation

where P\.(ti) is the fraction of the 250 cancers which have Gompertzian
parameters l>less than or equal to />,.This process defines the probability
distribution of b. Using PL(t) from Bloom and reasonable initial values
of N(0), NL, and ;V(<),
the distribution was found to be approximately
log-normal. By iteration, values of A^O), N_,
M00), and the mean and
standard deviation of b were found so as to minimize the least-squares
fit of loge(A)to the lim (/>,)values calculated above. The fit to the actual
data of the model so generated was confirmed by simulation of individ
ual growth curves. The model is as follows: A value of >
is chosen
randomly from the derived log-normal distribution and I, is calculated
such that /V(fi)= NL. The array of values of f
is used to estimate Pi(t)
by standard actuarial methods (29), and is graphically compared with
PL(t) from the Bloom data.
The second data set used by Speer is from Heuser et al. who present
data for 109 primary breast cancers (in 108 women) diagnosed among
10,120 screening mammograms (20). 45 lesions were discovered on
initial examination. Of the 64 remaining cases with diagnostic mam
mograms, 32 had had previous mammograms that retrospectively dem
onstrated measurable tumors. The authors estimate that these 32 ex
amples represent the slowest-growing 23% of cancers in their series,
with the remaining 77% growing too rapidly to remain undiagnosed
clinically between two widely spaced mammograms. Nine of the 32 had
such similar measurements in the two consecutive examinations that
growth could not be documented. For the 23 cancers that did grow to
a measurable degree the authors provide mutually perpendicular di
ameter values (L for length and W for width, such that L~>W} and the
date of each of the first and second measurements.
The Heuser data are analyzed here as follows: The time between
dates ti is calculated in months; each tumor volume is estimated as the
volume of revolution of an ellipse by (ir/6)-/,-Wh N(Q) is set at the
first volume; N(tu is set at the second volume; using the value of jV()
determined by the Gompertzian fit to the Bloom data, />,is calculated
by the Gompertz equation.
The third data set cited by Speer concerns the growth of micrometastatic foci of breast cancer following removal of a primary tumor
by Halsted radical mastectomy. In 1975 Fisher et al. (22) published the
10-year results of a National Surgical Adjuvant Breast Project trial of
postoperative chemotherapy compared with placebo for patients with
Stages I or II disease (regional disease not advanced and no evidence
of mtastasesexcept to axillary lymph nodes in Stage II). For 370
placebo-treated women at 5 years and 333 at 10 years the percentage
of free local or regional recurrence or mtastaseswere estimated by the
method of Cutler and Ederer (30). These are graphed in Fig. 3 for three
subgroupings by axillary lymph node positivity at the time of mastec
tomy: all nodes negative, one to three positive, or four or more positive.
The model of this paper is applied to the Fisher data by the same

method of simulation used to confirm the fit of the model to the Bloom
data, with three exceptions. The limiting event, recurrence, is set at a
tumor size .YK< V,; a variable percentage of patients are assumed to
be cured [i.e., N(0) = 0] by mastectomy; for the individuals who are not
cured A(0) is allowed to vary so as to give the best least-squares curve
fit to the probability of recurrence I'M) as a function of time t after
mastectomy.

RESULTS
By the above methods the Bloom data are found to be
consistent with the Gompertz equation with N(0)
4.8 x IO9
cells (almost 5 cc of densely packed tumor cells), jV(oo)= 3.1 x
IO12cells (3.1 liters), a lethal tumor cell number of NL = IO'2
cells (one liter), and, expressing t in units of months, a lognormal distribution of parameter
with mean Ion,(/>) of 2.9
and a standard deviation of log,(e) of 0.71. The line in Fig. \A
is the fit of this model to the Bloom data. Precise fit is seen at
all data points except the 86%-alive point at 1 year, where the
model predicts a 91.6% point. The Speer model underpredicts
this point to a comparable degree. Hence, the simple Gompertz
equation fits data for unperturbed breast cancer growth from
onset of breast mass to lethal tumor size.
Fig. IB presents sample growth curves simulated by the
Gompertzian model. Chosen for illustrative purposes are rep
resentatives of the 10th, 30th, 50th, 70th, 90th, and 99th
percentiles, ordered by rapidity of growth. These curves may be
compared directly with the points of 90, 70, 50, 30, 10, and 1%
survival in Fig. \A.
The probability density curve for loge(A) from the Gomper
tzian fit to the Bloom data is shown in Fig. 2. Graphed for
comparison are the 23 values for b\ calculated by the method
described above using the Heuser data. These values fit within
the lower 15% of the distribution of A, which corresponds well
with Heuser's estimate of 23%.
Fig. 3 presents PR(t) postmastectomy. The points are the
actual data and the lines are the predictions of the Gompertzian
model using the same probability density of \og,(b) and the
same ./V(oo)as derived for the Bloom data. The tumor size at
diagnosis of relapse is set at jVR= 10" cells. For node-negative
patients the best-fit parameters are JV(0) = IO2, 74.7% cured;
for the one to three positive node group jV(0) = IO4, 33.5%
cured; for patients with four or more involved nodes, jV(0) =
1.7 x IO7, 12.5% cured. The model not only fits the data points
well, but does so with sigmoid curves that simulate the shape
of actual clinical observations (31).
DISCUSSION
The ability of the Gompertzian model with variable parame
ter h to simulate clinical data demonstrates that the complexi
ties of the Speer model, which are unconfirmed experimentally,
are unnecessary theoretically as well. Even with fixed N(Q),
jV(oo), and fixed tumor size at event (recurrence, death), the
Gompertzian model provides a remarkably close fit to obser
vations. These fixed values are simplifying assumptions that
may account for the slight deviations of the model from the
data. While it has been previously observed in experimental
animals that b varies more widely than does N()
between
individual tumors of given histological type, 7V(<)
does, never
theless, vary. Indeed there may be a nontrivial functional rela
tionship between b and jV()
(12). In addition it is clear from
clinical experience that \(0) at first symptom is variable, and
it is unreasonable to assume that 7V(0)after mastectomy should
be constant in all individuals. Also, the tumor size N(t) at

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GOMPERTZIAN BREAST CANCER MODEL

iiir 'iiiiir

I .O

0.8

iiii 11

0.4

Bloom dato (1962)

0.3

Fit of model

o Heuser data (1979)

Fit of model to
Bloom data

0.6
0.2

04
O.I

0.2
O

!-

1-

IT"-?q- ' n ' og

8
10 12 14 16

Ql

oL<

.001

.01

.1
LOG,0(b)

Fig. 2. Probability
liiiiiiiiiiiii

density of Gompertzian parameter. The solid line represents

the probability density of Gompertzian parameter ft derived from the curve fit to
data as shown in Fig. 1. Parameter A is seen to be log-normal with mean log*(ft)
of-2.9 and standard deviation of log.(ft) of 0.71 (with time in the Gompertzian
equation expressed in months). The small circles are 23 data points for parameter
ft calculated from two-point mammographie data (20), using the model derived
to fit the survival data of Fig. I. The circles are expected to belong approximately
in the lower 23% of the cumulative probability distribution and indeed do fall in
the lower 15%.

024

10

12

14

16

YEARS OF GROWTH FROM ONSET OF SYMPTOMS

Fig. 1. Survival of untreated women with breast cancer. A, squares represent
the percentage of patients surviving per year after onset of symptoms for 250
women with untreated breast cancer (21). The solid line is the Tit of the Gompertzian model detailed in the text. Excellent fit is evident. B, solid lines represent
growth curves (tumor cell number as a function of time of growth) for selected
individual cancers simulated by the Gompertzian model which generated the
curve-fit in A. Ranking the simulated tumors in order of rapidity of growth, the
illustrations represent the 10th, 30th. SOth, 70th. 90th. and 99th percentiles. Each
tumor is assumed to be lethal at IO'2 cells (1 liter). Since 90% of the tumors reach
lethal size after the tumor representing the 10th percentile does, 90% of patients
would
expected
tocells,
survive
timerelationship
point at which
the 10thcurves
percentile
tumor be
reaches
!()''
etc. past
Usingthethis
the growth
of B
should be directly compared with the survival estimates of the line in I.

relapse or death varies between individuals, and might, in fact,

be partially dependent on the tumor growth rate. For example,
the slight overprediction by the Gompertzian model of the
percentage of Bloom's patients surviving at least 1 year may be
because rapidly growing tumors are lethal at a smaller size than
indolent cancers. The failure to demonstrate growth on serial
mammograms for nine tumors in the Heuser data set may
illustrate the imprecision of the estimation of A^O)from clinical
data: the diameter measurements from the first mammogram
may have included benign or premalignant tissue, or edema,
with only a component of actual neoplastic cells. Since breast
cancers frequently arise from areas of carcinoma-/ situ or
hyperproliferative fibrocystic disease, this possibility is tenable.
Allowance for variability in ./V(O),./V(),
and N(t) at relapse or
death could permit the Gompertzian model to simulate clinical
observations even more accurately than seen here. The inclusion
of additional parameters, however, must be based on carefully
analyzed, actual observations, so as to avoid the dangers of
overdetermination.
The Gompertzian parameters used here to fit the Bloom data,
and shown to be consistent with the Heuser and Fisher data
sets, are appropriate for an in vivo model, and must not be

*,*, Fisher data (1968!

Fit of model

2468
YEARS AFTER MASTECTOMY
Fig. 3. Disease-free survival for women following mastectomy. The data points
represent actuarial disease-free survival following radical mastectomy for women
with no positive axillary lymph nodes (A), one to three positive nodes (),and
four or more positive nodes ()
(22). The solid lines are the fits of the Gompertzian
model detailed in the text. The model fits the data with realistically shaped curves.

compared too strictly with such in vitro estimates as provided

by Salmon (19). Intact host mechanisms in vivo may add
significantly to the cell-loss factor, which serves to slow clinical
growth (32). Indeed, the relationship between in vitro measure
ments and in vivo growth characteristics of the same neoplastic
tissue may be a novel approach to the estimation of cell loss
and perhaps the efficacy of host defense.
The Gompertzian model simulates time-to-recurrence curves
after mastectomy by assuming that A'(O) and cure rate is a
function of the number of involved nodes at the time of surgery.
The analysis presented here thereby agrees with Skipper that
the residual N(Q) after mastectomy is greater when the number
of positive nodes is greater (33). The Speer model, in contrast,
attaches greater importance to the hypothesis of a positive
linear relationship between the number of micrometastatic sites
and the degree of nodal positivity. While a positive relationship
between N(0) and the number of different metastatic sites is
plausible, the Gompertzian model finds this hypothesis unnec
essary to explain the data. It is of note that Speer's linear
relationship

was fit by the assumption

of an average of two

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GOMPERTZIAN

BREAST CANCER MODEL

involved nodes in the group of patients with one-to-three posi

tive nodes, and five involved nodes in the four-or-more node
category. This assumption may be gratuitous. In addition, clin
ical experience with Stage IV disease discloses no major differ
ence in the spectrum of metastatic sites involved as a conse
quence of the prior nodal status (31, 34).
The Speer model advises postsurgical adjuvant chemotherapy
of prolonged duration so that chemotherapy exposure may
coincide with the hypothesized growth spurts. This recommen
dation has influenced the interpretation and design of clinical
trials (35). Yet prudence in this regard is indicated by several
considerations. Exponential and Gompertzian tumors should
be treated early and intensively for best results (15). For breast
cancer the parsimonious Gompertzian model is here shown to
simulate clinical data as well or better than alternative models,
which must afford it at least equal credence as regards clinical
extrapolations. Secondly, pending the completion of ongoing
clinical studies (36), currently available data fail to demonstrate
significant advantage from prolonged adjuvant chemotherapy
with a single drug combination, although some finite limit to
regimen brevity without loss of efficacy may well be defined by
future research (37, 38). Lastly, if the growth spurt postulated
by Speer were to occur, it would more likely be due to the
emergence of an aberrant clone than a change in the growth
kinetics of the entire population. While it is conceivable that
this aberrant clone might be more chemotherapy sensitive than
the parent cells by virtue of a higher growth fraction, it might
also be more insensitive as a consequence of randomly acquired
biochemical drug resistance (2). Hence, attempts toward erad
ication of the parent population prior to the emergence of this
potentially resistant clone would seem to be more fruitful than
delays in therapy. Indeed, there is no reason to suppose that
the parent population itself would be more sensitive to therapy
at a time after the emergence of the more rapidly growing clone
than before, so that even if the new clone were chemotherapy
responsive, the parent population would be no easier to cure
later rather than sooner. Therefore, even if the Speer model
were valid phenomenologically, intensive chemotherapy applied
immediately against minimal disease would still be more rea
sonable than prolonged low-dose or delayed treatment. Argu
ments in favor of immediate, intensive induction chemotherapy
followed by cross-over, intensive consolidation have been pre
sented elsewhere (2).
Since the sole intention of this paper is to demonstrate that
an unadorned Gompertzian model is sufficient to simulate
clinical data, a high degree of confidence in the precision of the
estimated parameters is neither meant nor justified. Such re
finements as the inclusion of variable jV(oo),jVL,and NR would
seem to be required to produce a more intuitively satisfactory
model. The impact of such modifications on the probability
density of b remains to be determined by further research.
Nevertheless, it is of speculative interest to note that setting
jV(0) = 1 and N(t{) = 4.8 x IO9, with N(oo) and the probability
density of \og,(b) as above, that the 95% confidence limits of t,
range from about 6 or 7 months to about 9 years, with a median
of about 2.25 years. This is a shorter duration of preclinical
growth than is usually assumed. Epidemiological data relating
the carcinogenic influence of short-exposure radiation to the
incidence of breast cancer would suggest a longer lag period
(39). This divergence is consistent with the concept of a timeconsuming precancerous state induced by the radiation, fol
lowed by a second, perhaps random, event associated with the
initiation of the Gompertzian growth of the actual malignancy.
Primary carcinogens other than radiation could also operate

according to this paradigm (23). Such a concept could relate

directly to attempts to alter or reverse the precancerous state
with pharmacological or micronutrient interventions.
The Speer model is innovative and thought provoking. At
present, however, there is insufficient evidence to abandon the
Gompertzian model for human breast cancer. Further refine
ments of the model presented here may well yield better esti
mates of the volume of the tumor residual after surgery or of
the average duration of growth preceding clinical presentation.
Nevertheless, no current model fits human or animal data better
than unadorned Gompertzian growth. The therapeutic impli
cations of other models in general, and the Speer model in
particular, should be interpreted and applied with caution.
ACKNOWLEDGMENTS
I thank Dr. James F. Holland for his critical review of this manuscript
and Rita B. Morales for her secretarial assistance.

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A Gompertzian Model of Human Breast Cancer Growth

Larry Norton
Cancer Res 1988;48:7067-7071.

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