Clinical and translational relevance of intratumor heterogeneity

Abstract

Intratumor heterogeneity (ITH) is a driver of tumor evolution and a main cause of therapeutic resistance. Despite its importance, measures of ITH are still not incorporated into clinical practice. Consequently, standard treatment is frequently ineffective for patients with heterogeneous tumors as changes to treatment regimens are made only after recurrence and disease progression. More effective combination therapies require a mechanistic understanding of ITH and ways to assess it in clinical samples. The growth of technologies enabling the spatially intact analysis of tumors at the single-cell level and the development of sophisticated preclinical models give us hope that ITH will not simply be used as a predictor of a poor outcome but will guide treatment decisions from diagnosis through treatment.

Keywords: clonal interaction; intratumor heterogeneity; single-cell technologies; treatment resistance; tumor plasticity.

Figure 1.. Subclonal evolution during cancer progression and therapy resistance.

(A) Fish plot illustrating subclonal dynamics during tumor progression and selection by cancer therapies. Every color represents a different subclone matching cell colors in (B) at the time of diagnosis and in (C) at relapse. (B) During tumor development, an initiated neoplastic cell population, defined by genetic or epigenetic characteristics, will give rise to a variety of subclones, generating a heterogeneous tumor by the time of diagnosis. Interactions between the emerging subclones, either direct or indirect via the microenvironment, will also influence their phenotype and fitness for example via the secretion of different factors (e.g., angiogenic, growth, and proteolytic). Subclonal interactions can be negative where the different subclones are competing for limited resources and secrete factors that will limit the expansion of other subclones (i.e., clonal competition). In contrast, a subclonal cooperation can also be present where a subclone produces a factor that promotes the growth or invasive properties of other subclones. (C) Different subclones may also respond differently to treatment, leading to the selection for a limited set of subclones with preexisting or acquired therapeutic resistance. Subclones resistant to treatment (here depicted in red, purple, and green) will be selected leading to relapse. Created with BioRender.com

Figure 2.. Liquid biopsy versus tissue biopsy: assessment of intratumor heterogeneity in genomic alterations.

In this illustration of a patient with metastatic disease, both traditional tissue biopsy as well as liquid biopsy, obtained via peripheral blood testing, are depicted. (A) Tissue biopsy of the liver lesion may yield both DNA without alterations (indicated by pink helices) and tumor somatic mutations (as indicated by orange mutant helices). (B) Biopsy of the hip lesion may also reveal a tumor somatic mutation (indicated by green mutant helix) that may be different than the mutations seen at other metastatic sites. (C) Biopsy of a different metastatic site, such as a lung lesion, may reveal yet another unique tumor somatic mutation (indicated by the blue mutant helix). (D) In this liquid biopsy plasma sample, mutations from multiple metastatic sites are detected (as indicated by both the orange mutant helices and the blue mutant helix). This is an advantage over single-site metastatic biopsy, which would have captured only the somatic mutations in the one lesion that is biopsied. However, liquid biopsy may not detect genomic alterations from every metastatic site. For example, the mutation indicated by the green mutant helix is not detected in this patient’s plasma sample. Created with BioRender.com

Figure I.

(A) In this hypothetical case study, the patient in Case 1 has a tumor that is homogenous in HER2 expression while the patient in Case 2 has HER2-heterogeneous disease. In current practice, both patients will be treated with neoadjuvant chemotherapy and HER2-targeting therapy. At the time of surgical evaluation, Case 1 is likely to have a pathologic complete response. However, Case 2, with HER2 heterogeneity, is more likely to have residual disease. (B) A potential future strategy may apply novel treatment regimens that are more effective for patients with HER2 heterogeneity. Created with BioRender.com