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Darwin’s Clinical Relevance
Samuel Hellman,
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois.
volution is the dominant fact of biology,’’ stated Nobel laureate
and codiscoverer of the structure of DNA, James D. Watson1
at a recent meeting at the University of Chicago. Although there has
been a great deal of interest in the evolution of cancer, it has been
focused primarily on preclinical events; however, these concepts
apply as well to the clinical manifestations of cancer. To design a
strategy for cancer management, one must have a model of the disease. For such a model to be useful it must be consistent with what
we already know, especially with what Watson describes as ‘‘the dominant fact of biology.’’ We must understand what evolutionary theory
both states and implies before we can apply it in the clinic. What
follows is a discussion of the clinical relevance of evolutionary concepts as they bear on the development of a cancer, its natural history
and prognosis, and to determining appropriate therapeutic strategies.
Address for reprints: Dr. Samuel Hellman, The
University of Chicago, 5758 South Maryland Avenue, MC 9001, Chicago IL 60637-1470.
Received November 13, 1997; revision received
March 4, 1997; accepted March 4, 1997.
Darwin’s Theory
The mechanism by which species evolve as explained by Darwin’s
theory of evolution is, as Ernst Mayr2 suggests, really five related
theories. First, organisms are transformed with time; they are not
fixed but continue to change. The parallel in oncogenesis is the notion
of cancer progression, an acquisition of the characteristics of increasing malignancy that continues throughout the natural history of the
cancer. Second, all groups of organisms can be traced to a common
ancestor; this, the theory of common descent, is reflected in the clonal
origins of cancer. Third, species multiply, diagrammed usually as a
branching tree, the result of geographically isolated founder populations and differing selection pressures. In contrast, cancer appears
more like a ladder then a tree. The appropriate evolutionary analogy
is called ‘‘convergent evolution.’’ Convergent evolution means that
similar selection pressures lead to similar phenotypes, but not identical genotypes. There may be similar mutations, the specific order of
mutation may be different, or there may be entirely different mutations resulting in similar phenotypic expression. For oncogenesis, this
is consistent with phenotypically similar tumors arising in the same
tissue while allowing for the variation observed in the genotypes and
in the temporal order of mutations. As Dennett suggests,3 ‘‘convergent
evolution is...overwhelmingly good evidence of the power of natural
selection.’’ Image-forming eyes have been found to have evolved independently numerous times in nature; perhaps 40 to 60 times in
invertebrates.4 Man and octopus have quite similar eyes, but have
evolved independently. Other examples of the power of a good solution is the use of echolocation in both bats and whales as a method
q 1997 American Cancer Society
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of sensing the environment. Arthropod respiration has
evolved quite separately in different species but the
phenotypic results are quite similar because as deDuve
suggests5 ‘‘inherited was a body plan that admitted
only one solution...or perhaps, favored this solution
over all others.’’ A remarkable example of the power
of convergent evolution is the independent evolution
of three different species of periodic cicada6 in which
each has a 13- and 17-year variety. Because both 13
and 17 are prime numbers, it is suggested that these
evolved in preference to, for example, a 15-year species because a parasite would be much less likely to be
able synchronize its life cycle to these prime numbers
whereas for a 15- year species, life cycles of 3 or 5
years would allow successful parasitizing of such cicada. These examples all demonstrate the power of
natural selection to seek successful solutions and use
them repeatedly. Similarly, the cancer phenotype has
four cardinal characteristics: growth, angiogenesis, invasion, and metastasis. There are a number of mutational paths that will allow the expression of these
The fourth of the related theories comprising the
theory of evolution suggests that evolution is gradual
rather than saltational. This has important connotations for the nature of tumor progression. Species
evolve with time to more fit organisms, more adapted
to the environment. For tumors this suggests that tumor evolution is not determined by a single event but
rather by a number of successive evolutionary
changes, each of which must be at least neutral, but
preferably contributes a competitive advantage. There
is some disagreement as to how important saltational
events are in evolution. Proponents argue that there
are long periods of quiescence with infrequent large
changes. Gould and Eldredge called this ‘‘punctuated
equilibria’’ 7 whereas critics have called this ‘‘evolution
by jerks.’’ Without entering this dispute, there are
some oncogenic correlates of both gradual and abrupt
progression. Some leukemias and sarcomas appear to
be the result of one or at most a few events. This does
not appear to be the case for the common carcinomas,
which require a large series of genetic changes.8 – 11
The fifth related theory according to Mayr2 is the
theory of natural selection. Abundant production of
variation and natural selection are the important engines of evolution. Darwin in his ‘‘Origin of the Species’’ 12 states, ‘‘as many more individuals of each species are born than can possibly survive, and as consequently there is a frequently recurring struggle for
existence, it follows that any being, if it vary in any
manner profitable to itself, under the complex and
sometimes varying conditions of life, will have a better
chance of survival and thus be naturally selected. From
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the strong principle of inheritance, any selected variety
will tend to propagate its new and modified form.’’
Cancer results from the abundant production of genotypic changes and selection that allows the evolving
malignant clone to increase its malignant capacities.
Contributions of the New Biology
There has been an explosion of biologic information
regarding carcinogenesis that should be understood
and placed in a consistent framework. These discoveries offer insights into how tumors form, progress
(evolve), and might best be managed. They begin with
the important chromosomal abnormalities13 and associated genetic instability14 that are now recognized as
characterizing cancer. In addition to these morphologic changes in chromosomes, specific genetic abnormalities have been identified. These include the dominant-acting oncogenes and suppressor or recessiveacting oncogenes that are consistent with mendelian
genetics. It is presumed that a dominant lesion results
from the acquisition of a new capacity, whereas a recessive lesion is the loss of some tumor-inhibiting protein. The latter requires that both genes are mutated
to lose the capacity to produce the suppressor. This
notion was first applied to inherited cancer in the twohit hypothesis of Knudson.15 He suggested that tumor
predisposition requires the loss of both alleles and that
hereditary cancer predisposition occurred when one
of these losses was inherited. Examples of this are familial retinoblastoma observed in children and the inherited mutation in the p53 gene responsible for the
various tumors observed in the Li-Fraumeni syndrome. RB, the gene associated with retinoblastoma,
and p53 genes are prototypic suppressor oncogenes.
Cancer has been shown to require a cascade of
mutations in which it appears that there may be significant variation in the mutations present and in their
order of production. Some mutations are more important than others because not only do they result in
the required phenotypes, they facilitate other phenotypic changes as well. A common type of facilitating
mutation that contributes to oncogenesis is one that
results in alteration in DNA repair. DNA repair deficiency has been shown to increase the likelihood of
tumors in certain heredity diseases (Table 1). The cell
cycle contains a number of ‘‘check points’’ at which
the DNA is scrutinized for damage and either repaired
or cell death initiated (apoptosis). Failure of these repair mechanisms has assumed an increasingly important role in the understanding of cancer evolution
as demonstrated in the different diseases of DNA repair. The genomic surveillance allows repair but appears to favor apoptosis when the DNA damage is
great or too important a cell (such as certain lympho-
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Darwin’s Clinical Relevance/Hellman
Oncologic Examples of the Three Required Evolutionary Activities: Mutation, Selection, and Amplification
Mismatch repair defect
Helicase mutation
Werner’s syndrome
Bloom syndrome
Repair defects
Ataxia telangiectasia
Xeroderma pigmentosum
Failure of checkpoint pause
p53 Li-Fraumeni
Loss of apoptosis
Metastatic colonization
Continued proliferation
LOH of recessive growth inhibitors
Loss of senescence
Loss of terminal differentiation
LOH: loss of heterozygosity.
cytes and germ cells16) is affected to chance incomplete repair.
The mechanism of normal cell senescence has
been related to progressive shortening of the telomere.17 Tumor cells express the enzyme telomerase,
allowing them to continue effective chromosomal replication and thus avoid senescence.18 The appearance
of telomerase is a relatively late event in tumorigenesis. Because telomerase production is a characteristic
of many tumors, but few normal cells,19 affecting telomerase function offers obvious therapeutic opportunities.
Defects in DNA repair, loss of check point surveillance, even the loss of senescence may provide a opportunity for ‘‘hyperevolution,’’ but increased mutations even with the preservation of the mutations in
clones not undergoing senescence does not cause evolution to cancer without selection pressure favoring
the evolving cancer. In the evolution of species there
must not only be mutations but these must be selected
for and amplified. Oncogenesis has similar requirements. Cancer is characterized by growth, invasion,
and metastasis. For any malignant transformation cellular proliferation is necessary, for without such proliferation, one of the necessary conditions- growth-cannot be achieved. Increases in cell proliferation also
facilitate tumor progression because they allow more
opportunities for mutation. Increased proliferation
can result in both increased metastagencity20 (Table
2) because tumors further in their progression are
more able to metastasize, and in increased tumor virulence because the more rapid proliferation will cause
tumors to exhibit their malignancy over a shorter period of time. There also must be loss of senescence
and a decrease in terminal differentiation for if all cells
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Virulence—pace or rate of disease growth, dissemination, and clinical manifestation
Metastagenicity—ultimate likelihood and extent of distant metastases
die or mature the altered clone will die out. Terminal
differentiation can be assessed clinically by histologic
examination of the tumor with grade being the accepted method of describing the state of tumor differentiation. Tumors must also invade to exhibit their
malignancy and must be able to colonize at a distance.
Continued growth, invasion, and metastases are the
characteristics that provide cancer with a selective advantage. They all appear to require the ability to induce a blood supply (angiogenesis.).21
Loss of apoptosis will facilitate oncogenesis, but
it is not required for it. Apoptosis serves to preserve
the undamaged genotype; its loss will allow greater
mutational variability to persist. Genetic instability favoring carcinogenesis can also be the result of DNA
repair deficiencies. A decrease in repair allows more
mutations to persist but the likelihood and extent of
mutations depends on both the presence and the fidelity of the repair process. An effective but imprecise
repair process, although allowing survival, may actually favor oncogenesis because it will allow the persistence of inaccurately copied genes. Genetic alteration
can be produced by a variety of both environmental
and iatrogenic mutagens. It is believed that the former
is of major etiologic importance to the development
of human cancer. The latter is demonstrated in the
emergence of therapy-induced tumors in long term
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survivors previously treated with radiation or chemotherapy.
Clinical Implications
Tumor size
There are important clinical implications to be appreciated when considering tumor progression in darwinian terms. Recognition of tumors early in their evolution becomes profoundly important. The extent of
tumor progression should be correlated with tumor
size because the smaller tumor is likely to have had
fewer of the genetic alterations in the malignant cascade. More correctly, the correlation should be with
the point in the evolutionary process at which the tumor resides. Size and stage within any specific tumor
type should be roughly correlated with the extent of
this process. There is evidence of progression in the
studies of chromosomal abnormalities and specific genetic changes in both dominant and suppressor oncogenes as a function of tumor stage that is consistent
with this concept.8 – 11 On average, small tumors should
be more curable by radiation, chemotherapy, or hormonal treatment because there should be fewer clonogens present, they should be proliferating slowly having experienced fewer facilitating mutations, or, if they
are proliferating rapidly, they should have a high cell
loss due to more terminal differentiation. Because
these small tumors then will be more likely well differentiated with a high cell loss and/or less proliferation,
they should have less clonal expansion between therapeutic treatments, an important consideration for
fractionated radiation and for chemotherapy administration. Clinical evidence is consistent with these differing characteristics of tumors as a function of size.
Koscielny et al.22 reported that as tumor size increased
the proportion of Grade 3 breast carcinomas increased
and that of Grade 1 carcinomas decreased. Similar
findings have been reported by Tabar et al.23 in the
two-county Swedish mammography trial. McNeal et
al.24 demonstrated an increase in Gleason grade with
increasing prostate carcinoma volume.
Small tumors are more likely to have the apoptotic
mechanism preserved. p53 mutations (the most common mutation observed in cancer) are present in ú
50% of human cancers. The likelihood of p53 mutations increases with tumor grade and stage.16 Although
the kinetics differ in different tumor types, the general
rule of p53 mutations increasing as tumors progress
is present in all types studied. bcl-2 and related genetic
abnormalities also appear to correlate with tumor progression (Olopade, unpublished data). According to
this application of darwinism to oncogenesis, small
tumors should be less likely to have metastasized because there is less progression and therefore less likely
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acquisition of the capabilities required for seeding and
growth at a distant site. Tabar et al.23 and Koscielny
et al.22 have shown that the likelihood of metastasis is
a direct function of tumor size.
As Folkman has shown, angiogensis is central to
the processes of growth and metastasis.21 The presence of areas of angiogenesis appears to be heterogeneous within tumors and prognosis is correlated with
the blood vessel density present in the most dense
region.25,26 Heimann et al. have shown that the density
of these most dense regions varies directly as function
of tumor size.27
Such considerations of tumor progression further
suggest that if metastases of small tumors have occurred they are more likely to be limited in number
and location. Such oligometastases28 are still amenable
to radical treatment. The clinical implications of finding metastases with small tumors will be different than
with large cancers. They are more likely to be oligometastases when the tumor is small rather than the
visible tip of the iceberg of polymetastases found with
more advanced tumors. This is evidenced by the
greater success of resection of metastases to the liver
when the primary colon carcinoma is of an earlier
stage.29 Presumably this is because the metastases
from an early stage primary tumor are more likely to
be oligometastases. Similarly, lymph node metastases
are more likely oligometastases when they are found
associated with small primary tumors rather than, as
suggested by Fisher, always being an indicator of distant disease.30 This is the case for breast carcinoma.20,31
The presence of 1-3 axillary lymph node metastases
does not confer an ominous prognosis when the tumor
is õ2 cm. This is not true when the same number of
metastases are present with larger tumors. The larger
tumors presumably have had more tumor progression,
are therefore more malignant, and have a greater facility for distant colonization. Although small breast carcinomas can be the source of multiple distant metastases, the presence of limited lymph node disease does
not predict for their presence, but rather is more likely
the fledgling attempt at metastasis by this early developing cancer.
Local control
Failure to eradicate all tumor or an intentional strategy
allowing tumor persistence will have deleterious effects. Most important, it will allow the residual tumor
to continue oncogenic progression. The systemic hypothesis (the basis for current therapeutic programs
allowing cancer persistence) argues that tumors, when
observed clinically, are of two types: they are either
incapable of metastasis, or if capable of metastasis,
have already metastasized.30 This is inconsistent with
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Darwin’s Clinical Relevance/Hellman
the application of what we know about species evolution to cancer because it suggests that a single event
causes the full malignant state or that the multiplicity
of events required have all occurred before clinical
recognition, after which the phenotype is fixed without
the opportunity for further malignant progression.
This systemic hypothesis assumes that the final cancer
phenotype is formed before clinical detectability. The
continued, progressive, and gradual nature of evolutionary progression is inconsistent with this view. It is
also in contrast to the proven benefit of mammography.32,33 A 30% reduction in breast carcinoma deaths
has been observed in the screening mammography
trials. This reduction in death was observed even before the widespread use of adjuvant systemic treatment. This implies that the locoregional treatment administered at the time of mammographic determination was more effective because between that time and
clinical detection metastases must have occurred in
30% of the patients. Because the average size of screen
detected tumors is approximately 1 cm and that of
clinically detected lesions ¢ 2 cm, significant tumor
progression likely occurs during this part of the natural
history of breast carcinoma.
That the persistence of breast carcinoma after inadequate local treatment has a deleterious effect can
be observed in the comparison of lumpectomy alone
with lumpectomy plus radiation or with mastectomy
in the NSABP study B06.34 There is a higher likelihood
for distant metastasis associated with the higher local
failure rate observed in the group having local excision
only. Fisher et al.34 state ‘‘Significantly or nearly significantly higher percentages of patients with node
negative breast cancer treated by mastectomy or
lumpectomy and breast irradiation remain free of disease and free of distant disease than patients treated
with node negative breast cancer treated by lumpectomy.’’ Similarly, the Stockholm Trial35,36 comparing
mastectomy to mastectomy plus radiation has shown
that the persistent local disease observed in the unirradiated group was correlated with an increased likelihood of distant metastasis. Both NSABP B-06 and this
trial are consistent with the deleterious consequences
of incomplete irradication of the primary tumor,
allowing continued tumor progression as well as permitting a continuing potential source of metastatic
cells to remain.
Markers of progression
Chronic myelogenous leukemia has a characteristic
9:22 translocation during the chronic phase but many
other genetic abnormalities are present during the
acute blast crisis. Markers of tumor progression correlate with outcome and with response to therapy. This
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has been shown in studies of microvessel density by
Wiedner and Folkman,25,26 Gasperini et al.,37 and Heimann et al.27 p53 mutations appear to be related to
chemoresistance.16 Although there are many markers
of proliferation, the relationship of rapid growth to
progression is complicated. Proliferation should correlate with progression because with more proliferation
there will be more opportunity for mutations and thus
more progression. These mutations can affect cell cycle time, terminal differentiation, or other phenomena
increasing cell birth or reducing cell loss. However,
differing proliferation rates in equivalently progressed
tumors should be reflected in increased tumor virulence but not increased metastagenicity. This is especially important when considering early stage cancers
and emphasizes the need for long follow-up. For example, studies of the prognostic importance of patient
age in T1 breast carcinoma reveal a greater tumor virulence in young patients but with continued follow up
the survival becomes equivalent to older patients.20
Similarly, proliferating cell nuclear antigen, grade, and
mitotic index predict for a difference in virulence but
not for metastagenicity (R. Heimann, personal communication and 38).
Because tumors evolve gradually, one would expect
cancer to be a disease of later life and very uncommon
in the young. The evolutionary penalty for a mutation
harming a multicellular organism decreases with age,
especially after the reproductive and childrearing period. Thus, there should be strong selection pressures
against cancer-causing mutations in the young that
decrease with advancing age. It is not an accident that
cancer incidence rises steeply after the fourth decade
of life. For cancers to occur early in life there should be
either a profound oncogenic event or some inherited
facilitating mutation such as the loss of one allele of
a suppressor gene. This latter, the Knudson hypothesis,15 appears to be correct for the hereditary cancers
retinoblastoma, Wilms’ tumor, and a rapidly enlarging
list including early onset breast carcinoma.
Finding an evolutionary role for the altruism observed
in many species has been an interesting question for
evolutionary biologists. Wilson39 has suggested that altruism can be considered as consistent with species
preservation and natural selection if it is the genome
rather than the particular organism that is the object
of evolution. If the sacrifice of an individual results
in increasing the survival probability of a colony of
organisms all sharing the same genotype, an evolutionary purpose has been served. The warrior ants in
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Differences in Cumulative Survival Fraction as a Function of
Differences in Individual Fractional Survival
Cumulative survival fraction N32
Daily survival fraction
Adapted from Hellman S. Cell kinetics, models, and cancer treatments—some principles for the radiation oncologist. Radiology 1975;114:219–23.
protecting the queen preserve their genes. Multicellular organisms can be considered to be the evolutionary
result of altruistic behavior in which genetically identical cells stay together and develop specialized functions rather than proliferating as independent clones.
This is a form of self-sacrifice by cells that become
somatic and do not contribute to the next generation.
Similarly, one may consider apoptosis a form of cellular altruism. In this case, a cell or even a developing
embryo will be sacrificed to preserve the object of evolution; the fidelity of the genome. Although some mutational activity favors evolutionary change, most mutations are either neutral or harmful. For example, p53
has been shown to be associated with surveillance of
the DNA. When at least one normal p53 allele is present, the fidelity of the DNA is monitored. If there is
too much damage, apoptosis occurs. In this fashion,
it acts as a guardian of the genome. Not only is loss
of p53 function related to tumor progression; knockout
mice in which both p53 genes are deleted have fewer
abortions and a greater number of malformed offspring after X-ray exposure.40 Thus, p53-related
apoptosis suppresses not only cellular mutations but
teratogenesis as well. bcl-xL , a potent inhibitor of
apoptosis, is correlated with markers of tumor progression such as grade and the extent of lymph node
involvement (Olopade et al., unpublished data).
The likelihood for apoptosis after exposure to radiation or chemotherapy may be the most important
determinant of successful treatment. Apoptosis results
in a 10 – 15% incremental cell kill with the usual 1.8 –
2.0-gray fractions43 and this effect persists with daily
administration. A 10 – 15% change in fractional cell kill
will have a 1000-fold difference in survival over a normally protracted radiation treatment regimen (Table
3). Similar considerations are obtained with chemotherapy and so it is not remarkable that one of the
factors most correlated with successful treatment is
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the presence of normal p53 function.12 Growth factor
deprivation also increases apoptosis even when the
p53 gene is not functional. The importance of
apoptosis provides intriguing therapeutic opportunities. It may also be relevant to the enhancement of
radiation effects observed when androgen deprivation
is combined with radiation therapy in the treatment
of prostate carcinoma,42 as shown in the Radiation
Therapy Oncology Group trial demonstrating an improvement in both local control and progression free
survival. Androgen deprivation and other hormonal
actions can cause apoptosis directly and may increase
the likelihood of an apoptotic response to radiation.
The theory of tumor progression and the resulting importance of early diagnosis and local tumor control
are relevant to the broader current debates concerning
prostate carcinoma management.
The important lesson of the application of darwinism
as applied to cancer is that evolutionary principles
apply. As species evolve, so cancer cells progress. Mutations and selection are crucial to both speciation and
cancer progression. The compelling clinical implication is that cancer is a genetic disease that changes,
becoming increasingly more malignant during the
clinical phase. Molecular pathology of the tumor offers
the promise of prognostic information and determination of appropriate therapy. Consistent with the implications of Darwin’s theory, early diagnosis is a vital
tool for successful therapy. It allows treatment of a
tumor with fewer clonogens and one that is less malignant because it has had less opportunity to evolve.
Because clinical cancer continues to progress (evolve),
maximal ablation of the primary tumor must be an
essential component of any therapeutic strategy.
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