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Naming disease states for clinical utility in prostate cancer: a rose by any other name might not smell as sweet

2017; Elsevier BV; Volume: 29; Issue: 1 Linguagem: Inglês

10.1093/annonc/mdx648

1569-8041

Andrew J. Armstrong, Emmanuel S. Antonarakis, Mary‐Ellen Taplin, William Kevin Kelly, Himisha Beltran, Karim Fizazi, William L. Dahut, Neal D. Shore, Susan F. Slovin, Daniel J. George, Michael A. Carducci, Paul G. Corn, Daniel C. Danila, Robert Dreicer, Elisabeth I. Heath, Dana E. Rathkopf, Guoqiang Liu, David M. Nanus, Mark N. Stein, Mitchell R. Smith, Cora N. Sternberg, George Wilding, Peter S. Nelson, Susan Halabi, Philip W. Kantoff, Noel W. Clarke, Christopher P. Evans, Axel Heidenreich, Nicolas Mottet, Martin Gleave, Michael J. Morris, Howard I. Scher,

Cancer, Lipids, and Metabolism

The letter by Pezaro et al. [1.Pezaro C.J. Omlin A. Mastris K. et al.Precision, complexity and stigma in advanced prostate cancer terminology: it is time to move away from 'castration resistant' prostate cancer.Ann Oncol. 2017; 28: 1692-1694Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar] emphasizes a preference for changing nomenclature in prostate cancer, particularly avoiding the terminology 'castration-resistant prostate cancer', given that it can be off-putting and objectionable to patients and providers. However, their letter does not frame the taxonomy of the disease accurately; nor does it address the patient benefit derived from appropriately describing the biology for scientific investigation, the regulatory framework for drug development, and how this taxonomy aligns patients, clinicians and researchers in their understanding of the patient's relevant biology within the continuum of his specific prostate cancer history. As such, until new findings evolve these issues, we advocate retaining the current terminology. The use of the term castration harkens back to the Nobel Prize winning researchers who first identified the dependence of prostate cancers on testosterone for growth. This seminal paper by Huggins and Hodges, entitled 'Studies on prostatic cancer. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate', changed our understanding of the disease and its treatment [2.Huggins C. Hodges C.V. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate.CA Cancer J Clin. 1972; 22: 232-240Crossref PubMed Scopus (537) Google Scholar]. As astute clinicians, they observed and reported that the benefits of castration were of variable frequency and duration, but that ultimately, virtually all tumors became resistant. Over the ensuing decades surgical castration was largely replaced by medical treatments that were therapeutically non-inferior, and the terminology to describe tumors that were progressing despite castrate levels of testosterone became more palatable but less accurate due to variations in the testosterone assays available. A key example is how physicians and scientists employed the term 'hormone refractory', implying that use of a 'hormonal agent' would be ineffective, and that the only options to consider would be a cytotoxic drug, palliative radiation therapy or supportive care. Moreover, responses to second-line hormonal agents, including estrogens, antiandrogens, ketoconazole and glucocorticoids were also reported, albeit of short duration, lending further ambiguity to both research and clinical interpretations. Another relatively inoffensive term was 'androgen independent', which also misrepresents the disease and its biology, implying that disease growth was activated by processes separate from the androgen receptor (AR), and that further AR-directed therapy would be futile. We now know this to have been entirely incorrect for the majority of patients [3.Chen C.D. Welsbie D.S. Tran C. et al.Molecular determinants of resistance to antiandrogen therapy.Nat Med. 2004; 10: 33-39Crossref PubMed Scopus (1960) Google Scholar] with the demonstration that drugs such as abiraterone and enzalutamide can extend life duration. PCWG2 and 3 realigned biology, drug development and clinical practice [4.Scher H.I. Halabi S. Tannock I. et al.Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.J Clin Oncol. 2008; 26: 1148-1159Crossref PubMed Scopus (1794) Google Scholar, 5.Scher H.I. Morris M.J. Stadler W.M. et al.Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3.J Clin Oncol. 2016; 34: 1402-1418Crossref PubMed Scopus (826) Google Scholar]. The guidelines classified patients based on the status of primary tumor, disease distribution, the measured level of testosterone in the blood and the prior therapies to which a tumor has been exposed. This integrated taxonomy aligned clinical research and clinical practice in a practical way that was easily recognized by patients, physicians, researchers, regulators and third-party payers. PCWG3 not only requires recognizing all previous exposures to treatments, which Pezaro overlooks, but also enhances accuracy of categorization by not simply grouping all patients as 'advanced', which, depending on the circumstances, could apply to the patient with T4 local disease, to the patient with bone-only disease, to the patient with visceral disease. Instead, PCWG3 creates a framework that describes patients who face similar clinical risks, and similarly reflects fundamentals of their individual biology. The clinical states framework has become an essential component of drug development, testing and approval. Regulatory bodies recognized that the category of castration-resistant metastatic disease described patients with similar clinical risk and unmet needs, and the words 'castration resistant' are used verbatim in the drug labels of the four life-prolonging therapies in prostate cancer patients because of this framework. The 'castration resistant' terminology was also used by ASCO in their clinical practice opinion on second line hormonal therapy for 'castration resistant' disease [6.Virgo K.S. Basch E. Loblaw D.A. et al.Second-line hormonal therapy for men with chemotherapy-naive, castration-resistant prostate cancer: American Society of Clinical Oncology Provisional Clinical Opinion.J Clin Oncol. 2017; 35: 1952-1964Crossref PubMed Scopus (39) Google Scholar]. The authors do rightfully point out that there is now increasing activity in the early non-castrate metastatic setting, before the emergence of castration resistance. Here again there is controversy as some classify these patients as 'castration sensitive' or 'castration naïve', which is also problematic in that the first implies the ability to 'predict' response before treatment, and the second excludes patients who have already received ADT in the neoadjuvant, adjuvant, or rising PSA (post-local treatment) setting and as such are not 'naïve'. Indeed, the advantage of the current PCWG3 taxonomy is that it does not presuppose sensitivity or resistance, but is descriptive of a patient's status based on prior treatment(s) a patient has received, and separately the current phenotype and genotype of the tumor and the patient. From a biologic standpoint, the CRPC grouping allows for the recognition of the crucial biologic differences that this disease state encompasses. We now recognize that castration resistant disease encompasses a multiplicity of molecularly defined subtypes that in turn lend themselves to sub-characterization as defined molecular states with potentially varying clinical utility. Included are tumors with the AR splice variant-7 (AR-V7) [7.Antonarakis E.S. Lu C. Wang H. et al.AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.N Engl J Med. 2014; 371: 1028-1038Crossref PubMed Scopus (1951) Google Scholar, 8.Scher H.I. Lu D. Schreiber N.A. et al.Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer.JAMA Oncol. 2016; 2: 1441Crossref PubMed Scopus (472) Google Scholar] and lack of response to secondary hormonal therapies such as enzalutamide and abiraterone. The presence of homologous recombination repair deficiency [9.Pritchard C.C. Mateo J. Walsh M.F. et al.Inherited DNA-repair gene mutations in men with metastatic prostate cancer.N Engl J Med. 2016; 375: 443-453Crossref PubMed Scopus (950) Google Scholar], including both germline and somatic aberrations, may define a molecular subset of patients that respond to platinum chemotherapy or PARP inhibition [10.Mateo J. Boysen G. Barbieri C.E. et al.DNA repair in prostate cancer: biology and clinical implications.Eur Urol. 2017; 71: 417-425Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 11.Rickman D.S. Beltran H. Demichelis F. Rubin M.A. Biology and evolution of poorly differentiated neuroendocrine tumors.Nat Med. 2017; 23: 1-10Crossref PubMed Scopus (121) Google Scholar]. In addition, up to 2%–5% of men with CRPC may harbor mismatch repair deficiency and/or microsatellite instability, either in the germline (Lynch Syndrome) or somatically acquired which predicts for sensitivity to PD-1 blockade [12.Le D.T. Durham J.N. Smith K.N. et al.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science. 2017; 357: 409-413Crossref PubMed Scopus (3808) Google Scholar]. Also included are the TP53/RB1-inactivated tumors with or without the neuroendocrine or anaplastic phenotype, which also may require a different therapeutic approach to achieve a favorable outcome [11.Rickman D.S. Beltran H. Demichelis F. Rubin M.A. Biology and evolution of poorly differentiated neuroendocrine tumors.Nat Med. 2017; 23: 1-10Crossref PubMed Scopus (121) Google Scholar]. AR driven tumors can be classified into ligand dependent or independent, and glucocorticoid-driven tumors may also exist [13.Arora V.K. Schenkein E. Murali R. et al.Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.Cell. 2013; 155: 1309-1322Abstract Full Text Full Text PDF PubMed Scopus (655) Google Scholar]. It is anticipated that other pathways may be able to further sub-classify patients, as non-AR dependent cells may pre-exist in patients and emerge over time during treatment progression [14.Robinson D. Van Allen E.M. Wu Y.M. et al.Integrative clinical genomics of advanced prostate cancer.Cell. 2015; 161: 1215-1228Abstract Full Text Full Text PDF PubMed Scopus (2012) Google Scholar]. Each of these molecularly based biologic subtypes provides new drug development and treatment opportunities within the present taxonomy, which is becoming increasingly important in guiding treatment selection. Prior therapy alone does not classify a patient. It is critical that clinical care will remain unchanged until therapeutic action is linked to a new molecular state. In practice, physicians already integrate disease manifestations such as pattern of spread (visceral, nodal, bone), presence of pain, functional status, bone only metastases and measures of disease burden and presentation (i.e. high volume mHSPC, low PSA producing aggressive mCRPC variants). For example, tumors that are proliferating in the absence of AR signaling, the AR indifferent tumors, also including small cell, neuroendocrine, anaplastic or aggressive-variant prostate cancer [15.Beltran H. Tomlins S. Aparicio A. et al.Aggressive variants of castration-resistant prostate cancer.Clin Cancer Res. 2014; 20: 2846-2850Crossref PubMed Scopus (271) Google Scholar], should ideally be redefined by the molecular alterations that are ultimately linked to the outcome to a specific therapy. Adding in clinical phenotypes, and outcomes for the individual patient can be optimized. The process of naming and classifying an entity to define a disease taxonomy is an expression of how we view, understand, study and treat that entity. A taxonomy represents the organization of knowledge to provide a framework that must serve patients beyond esthetics, helping them to better understand their disease, its biology, treatment options, and the potential for morbidity and mortality. Changing a taxonomy that arose from such a process might be justified if there was a new scientifically based understanding of the reasons prostate cancers grow despite low levels of serum testosterone. There is no doubt that terminology can and should evolve as new knowledge is generated to better understand the disease. Nor is there doubt that patients should participate in the development of nomenclature, although prostate cancer patients and investigators are not mutually exclusive groups. However, the driving force that impels changes in nomenclature and taxonomy should be a fundamentally altered scientific framework that is ideally based on clinical outcomes. The present framework is indeed becoming more complex but is not obsolete, and has been (and continues to be) highly efficient at defining the complexity of the disease at its later stages, leading to rapid drug development and approvals. The term castration resistant is not a term that we routinely use with all patients. More commonly, direct patient communications focus more on disease biology, genotypes/phenotypes, and their therapeutic implications for patient care. Before changing the taxonomy of this disease, Pezaro et al. should consider that the framework and its terminology have been the intellectual infrastructure that has supported significant scientific advances prolonging hundreds of thousands of patients' lives. While the authors articulate that the present terminology can be awkward, scrapping the taxonomy of the disease without a scientific basis may cause more patient harm than good. None declared.