A strategy for distinguishing optimal cancer subtypes

Abstract

Much attention is directed currently to identifying subtypes of cancers that are genetically and clinically distinct. The expectation is that subtyping on the basis of somatic genomic characteristics will supplant traditional pathological subtypes with respect to relevance for targeted therapies and clinical course. Less attention has been paid to the goal of validating subtypes on the basis of the distinctiveness of their etiologies. In this article it is shown that studies of individuals with double primary malignancies provide uniquely valuable information for establishing the etiologic distinctiveness of candidate tumor subtypes. Studies of double primaries have the potential to definitively rank candidate taxonomic systems with respect to their etiological relevance by determining which subtypes are most highly correlated in the double primaries. The concept is illustrated with data from studies of the concordance of estrogen and progestin status in bilateral breast cancers, where it is shown that double primaries are much more likely to be concordant with respect to estrogen receptor (ER) status than for PR status. The high concordance of ER status is consistent with a growing literature demonstrating the etiologic distinctiveness of ER1 and ER2 tumors.Much attention is currently being directed at the goal of classifying cancers into distinct molecular subtypes, using extensive genomic data that distinguishes the somatic characteristics of these subtypes.1,2 It is anticipated that sub-classifications based on molecular characteristics will lead to a better understanding of cancer biology, and better avenues for determining appropriate targeted therapies. 3,4 Efforts to validate the relevance of candidate subtypes have usually focused on establishing clinical distinctiveness on the basis of, say, different survival for patients in the subtypes, or by merely showing that the genomically determined subtypes differ systematically with respect to conventional pathologic criteria. It is reasonable to speculate, however, that subtypes that are genuinely biologically distinct are likely also to possess distinct etiologies. Conventionally, epidemiologists have examined the potential etiologic heterogeneity of cancer subtypes by comparing the candidate subtypes with respect to the presence of known risk factors for the cancer in question. 5 Because it is widely believed that many risk factors for cancer, especially genetic factors, have not yet been identified, this strategy is necessarily limited in scope. The thesis of this article is that optimal subtyping of cancer from an etiologic perspective can be accomplished without the need to know any risk factors, merely by studying the co-occurrence of the subtypes in series of patients with double primary malignancies.The ageing of the population, allied to a gradual increase in survival following cancer has led to a rapid increase in the occurrence of second primary cancers. In fact, over 16% of all cancers reported to the Surveillance Epidemiology and End Results (S...

Aspirin as adjuvant therapy for colorectal cancer—reinterpreting paradigms

“…More recently, the concept of Molecular Pathological Epidemiology proposed by Ogino et al 90,91 may provide a useful route in dissecting the interactive effects between tumour biomarkers, such as COX-2, and aspirin exposure. 90,91 This concept, similar to proposals by Begg et al 92 and Curtin et al, 66 combines traditional epidemio logical assessment of cancer risk factors, with traditional molecular pathology-with the aim of evaluating the impact of environmental exposures (such as, aspirin) on the molecular signatures of tumours. 92,66 This inter sectional approach may be useful in enabling researchers to tease apart the interactive effects of prior aspirin exposure, tumour location, MSI and CIMP status, COX-2 expression, and response to treatment.…”

“…90,91 This concept, similar to proposals by Begg et al 92 and Curtin et al, 66 combines traditional epidemio logical assessment of cancer risk factors, with traditional molecular pathology-with the aim of evaluating the impact of environmental exposures (such as, aspirin) on the molecular signatures of tumours. 92,66 This inter sectional approach may be useful in enabling researchers to tease apart the interactive effects of prior aspirin exposure, tumour location, MSI and CIMP status, COX-2 expression, and response to treatment. Furthermore, Molecular Pathology Epidemiology has the potential to provide interesting clues concerning the relationship between tumour molecular features, and the adaptive immune response.…”

Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression

“…Despite this anatomic independence, a number of studies have shown that synchronous and metachronous bilateral breast cancers tend to demonstrate concordance in expression status for the hormone receptors ESR1 (estrogen receptor-alpha), and PGR (progesterone receptor). 71 These data imply that, in bilateral breast cancer, independent primary tumors tend to evolve through similar carcinogenic pathways, compared to cancers arising in two different individuals.…”

“…13–17 Alternatively, it can be considered that synchronous primary tumors arise through the interplay between common etiologic contributors, such as genetic predisposition, microbial and environmental exposures, and lifestyle factors, which facilitate progression through certain common carcinogenic pathways. 65, 67, 71 Importantly, the latter model does not imply that the molecular features shared by synchronous tumors need to be present in the background ‘normal-appearing’ tissue.…”

Proceedings of the second international molecular pathological epidemiology (MPE) meeting

“…This facilitates the exploration of countless sub-typing options to identify the set or sets that possess the greatest evidence of heterogeneity. [64] He also explained the unique insights that can be obtained by investigating and correlating the mutational profiles of double primary malignancies,[123] and illustrated the concepts using studies of breast cancer, melanoma and kidney cancer.…”