References and Citation Map
Reference List and Citation Map
20 references [1], [9] core [10], [16] extended [17], [20] Paper 5
[1], [9] Original core references
[10], [16] Extended references (evidential gap-fill, Papers 1-4)
[17], [20] Paper 5 additions (PSA kinetics and natural history)
References [1], [9] form the original core spine. References [10], [16] address evidential gaps identified across Papers 1-4. References [17], [20] are additions supporting Paper 5 on PSA kinetics and natural history. Refs [5] and [6], Johansson and Albertsen, carry weight across both the autopsy/ecology papers and Paper 5; they are listed once in the core spine and their Paper 5 roles are documented in the citation map.
[1] Gatenby RA & Gillies RJ (2009). A microenvironmental model of carcinogenesis. Nature Reviews Cancer.
Founding paper of evolutionary oncology. Establishes that tumor cells evolve under environmental
selection pressures, not mutation alone, and that aggressive phenotypes emerge when ecological
conditions favour them. Directly supports the argument that maximal therapeutic suppression
accelerates evolutionary escape by restructuring the selection environment.
[2] Zhang J, Cunningham JJ, Brown JS & Gatenby RA (2017). Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nature Communications.
Clinical validation of adaptive therapy in mCRPC. Demonstrates that modulating treatment pressure
extends time to progression by maintaining sensitive cell populations as ecological competitors to
resistant variants. Uses significantly less total drug over the treatment course. The closest
clinical analogue to the Quiet Biology management framework.
[3] Aktipis CA, Boddy AM, Jansen G, et al. (2015). Cancer across the tree of life: cooperation and cheating in multicellularity. Philosophical Transactions of the Royal Society B.
Frames cancer as the re-emergence of ancestral unicellular behaviour when the governance systems
enforcing multicellular cooperation are disrupted. Establishes that maintaining tissue regulatory
integrity, metabolic, immune, structural, is itself a form of cancer control. Grounds the QB
argument that systemic health is biologically central to cancer management, not merely supportive.
[4] Franks LM (1954). Latent carcinoma of the prostate. Journal of Pathology and Bacteriology.
Original autopsy discovery demonstrating that microscopic prostate cancer is common in men dying of
unrelated causes. Establishes the foundational paradox: tumour initiation is near-universal in older
men; clinical progression is not. Anchors the argument that environmental conditions, not genetics
alone, determine whether latent cancer becomes lethal. Referenced across Papers 1, 3, 4, and 5.
[5] Johansson JE, Andrén O, Andersson SO, et al. (2004). Natural history of early, localized prostate cancer. JAMA.
Twenty-year outcomes from the Swedish observational cohort: the foundational long-term evidence that
most localized prostate cancer progresses slowly, with low disease-specific mortality in well- and
moderately-differentiated tumors over the first 10-15 years. Establishes that prostate cancer has a
natural biological tempo and that watchful observation is a defensible initial strategy for
appropriately selected patients. Provides ecological and natural history grounding in Papers 1, 3,
and 4; serves as primary evidential anchor in Paper 5 Section 2.
[6] Albertsen PC, Hanley JA & Fine J (2005). 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA.
Population-level outcome data showing that mortality risk varies dramatically by tumour grade.
Gleason 6 disease carries approximately 6% disease-specific mortality at 20 years; Gleason 8-10
exceeds 60-87%. Establishes grade as the primary biological signal for prognosis and reinforces
selective intervention over reflex treatment. Competing mortality analysis essential for older
patients. Cited in Papers 1, 3, and 4 as natural history support; central to Paper 5 Section 3.
[7] Fidler IJ (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews Cancer.
Revisits and formalises Paget’s seed-and-soil hypothesis, demonstrating that tumour behaviour
depends critically on host microenvironment (‘soil’) as well as tumour genetics (‘seed’).
Foundational support for the field control concept and the argument that the tissue environment is
an active determinant of tumour fate, not merely a passive substrate.
[8] Vander Heiden MG, Cantley LC & Thompson CB (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science.
Explains how metabolic context governs tumour growth dynamics, establishing that cancer cells
actively rewire metabolism to support proliferation. Supports the concepts of metabolic
permissiveness and metabolic constraint. Foundational reference for Paper 2 (Metabolism and
Epigenetics).
[9] Hanahan D (2022). Hallmarks of Cancer: New Dimensions. Cancer Discovery.
Updated hallmarks framework explicitly incorporating non-mutational epigenetic reprogramming,
unlocking phenotypic plasticity, and enabling conditions. Frames cancer progression as dependent on
system-level conditions, not solely cell-intrinsic mutations. Directly supports the central QB
thesis: mutations provide potential; environment determines expression. Referenced in Papers 1, 2,
3, and 4 as the synthesising theoretical anchor.
Evidential gap references incorporated following review of Papers 1-4.
[10] Sakr WA, Haas GP, Cassin BF, Pontes JE & Crissman JD (1993). The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. Journal of Urology.
Provides the specific age-stratified autopsy prevalence figures cited in Paper 1: histologically
identifiable prostate cancer in approximately 30-40% of men in their fifties, rising to more than
60-70% in men over 80. Anchors the quantitative claims that make the autopsy paradox concrete
rather than merely descriptive. Also cited in Paper 5 Section 1 to ground the biological
prevalence context.
[11] Mosquera JM, Mehra R, Regan MM, et al. (2009). Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clinical Cancer Research.
Documents the prevalence of TMPRSS2-ERG gene fusions in low-grade and incidental tumours,
establishing that canonical oncogenic alterations are present in latent prostate cancer. Directly
supports the Paper 1 claim that many latent tumours carry molecular features classically associated
with malignant potential, yet remain clinically silent.
[12] Kaelin WG & McKnight SL (2013). Influence of metabolism on epigenetics and disease. Science.
Establishes the mechanistic links between cellular metabolic state and chromatin-modifying enzyme
activity, covering acetyl-CoA, SAM, α-ketoglutarate, and NAD⁺ as epigenetic cofactors.
Foundational reference for the Paper 2 argument that metabolic reprogramming precipitates
epigenetic change rather than merely accompanying it.
[13] Ku SY, Rosario S, Wang Y, et al. (2017). Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science.
Experimental model demonstrating that RB1 and TP53 loss cooperate to enable lineage plasticity and
neuroendocrine transition under therapeutic pressure. Anchors the Paper 2 claim that
epigenetic and transcriptional flexibility is a prerequisite for lineage switching, and that
interfering with this flexibility reduces transition probability.
[14] Gatenby RA, Silva AS, Gillies RJ & Frieden BR (2009). Adaptive therapy. Cancer Research.
Introduces the formal adaptive therapy framework and the evolutionary double-bind concept.
Distinct from the 2009 Nature Reviews Cancer paper [1]; anchors the double-bind discussion in
Paper 4 and the ecological management argument in Paper 3.
[15] Kalluri R (2016). The biology and function of fibroblasts in cancer. Nature Reviews Cancer.
Comprehensive account of normal-to-CAF fibroblast transition and its disproportionate regulatory
consequences for epithelial growth, immune exclusion, and extracellular matrix remodelling.
Anchors the Paper 3 keystone species argument: stromal loss is ecologically catastrophic for
microenvironmental regulation.
[16] West J, You L, Zhang J, et al. (2023). Towards multidrug adaptive therapy. Cancer Research.
Extends adaptive therapy to multidrug protocols and reports on the Moffitt Cancer Center programme
including FRAME trial design. Anchors the Paper 4 claim that adaptive therapy is a live and
developing clinical programme, not a single historical proof-of-concept.
New references supporting Paper 5: PSA Kinetics and the Natural History of Prostate Cancer.
[17] Wilt TJ, Brawer MK, Jones KM, et al. (PIVOT Study Group) (2012). Radical prostatectomy versus observation for localized prostate cancer. New England Journal of Medicine.
First large randomized controlled trial comparing radical prostatectomy with observation in
clinically localized prostate cancer (n≈700, follow-up to 20 years). Primary finding: surgery did
not significantly reduce all-cause or prostate-cancer-specific mortality in the full cohort.
Survival benefit confined to higher-risk subgroups. Directly supports the Paper 5 argument that
immediate aggressive treatment does not improve outcomes for most men with low-risk localized
disease. Randomised confirmation of the Johansson and Albertsen observational findings.
[18] Hamdy FC, Donovan JL, Lane JA, et al. (ProtecT Study Group) (2016). 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. New England Journal of Medicine.
Largest randomised trial comparing radical prostatectomy, radiotherapy, and active monitoring in
PSA-detected localized prostate cancer (n>1,600, median follow-up 10 years, extended to 15 years
in subsequent analysis). Primary finding: prostate cancer-specific mortality approximately 1% and
not significantly different across all three groups at 10 years. Monitoring group showed higher
metastasis rates at 15 years but without proportionate mortality signal. Provides the most
comprehensive comparative harm data: prostatectomy carries significantly higher rates of urinary
incontinence and erectile dysfunction across follow-up. Establishes that the survival margin
between immediate treatment and active monitoring is narrower than clinical intuition has assumed.
[19] Carter HB, Pearson JD, Metter EJ, et al. (1992). Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA.
Foundational PSA velocity paper using stored serum from the Baltimore Longitudinal Study of
Aging. Demonstrates that men who subsequently developed prostate cancer showed significantly
higher rates of PSA rise in the years before diagnosis. Establishes PSA velocity (rate of change
per year) as a diagnostic and prognostic signal independent of absolute PSA level. Anchors the
Paper 5 argument that trajectory encodes biological information that a single measurement cannot
provide.
[20] D’Amico AV, Chen MH, Roehl KA & Catalona WJ (2004). Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. New England Journal of Medicine.
Demonstrates that PSA velocity in the year before diagnosis is an independent predictor of
prostate cancer-specific mortality, even after adjusting for grade, stage, and PSA level. Men with
pre-diagnosis PSA velocity exceeding 2 ng/mL per year face substantially higher disease-specific
mortality regardless of absolute PSA. Directly challenges the clinical habit of making treatment
decisions based primarily on PSA level. Anchors the Paper 5 argument that velocity is more
prognostically informative than level, and supports PSA doubling time as the primary kinetic
monitoring tool in the QB framework.
All 20 references mapped across all five papers. Colour coding: [1], [9] core (blue) [10], [16] extended (dark red) [17], [20] Paper 5 additions (green). Refs [5] and [6] are core references with primary analytical weight in Paper 5; they appear in both the Paper 1-4 and Paper 5 sections of the map.
[1], [9] original core [10], [16] gap references [17], [20] Paper 5 additions