Factors affecting the value of diffusion-weighted imaging for identifying breast cancer patients with pathological complete response on neoadjuvant systemic therapy: a systematic review

Abstract

This review aims to identify factors causing heterogeneity in breast DWI-MRI and their impact on its value for identifying breast cancer patients with pathological complete response (pCR) on neoadjuvant systemic therapy (NST). A search was performed on PubMed until April 2020 for studies analyzing DWI for identifying breast cancer patients with pCR on NST. Technical and clinical study aspects were extracted and assessed for variability. Twenty studies representing 1455 patients/lesions were included. The studies differed with respect to study population, treatment type, DWI acquisition technique, post-processing (e.g., mono-exponential/intravoxel incoherent motion/stretched exponential modeling), and timing of follow-up studies. For the acquisition and generation of ADC-maps, various b-value combinations were used. Approaches for drawing regions of interest on longitudinal MRIs were highly variable. Biological variability due to various molecular subtypes was usually not taken into account. Moreover, definitions of pCR varied. The individual areas under the curve for the studies range from 0.50 to 0.92. However, overlapping ranges of mean/median ADC-values at pre- and/or during and/or post-NST were found for the pCR and non-pCR groups between studies. The technical, clinical, and epidemiological heterogeneity may be causal for the observed variability in the ability of DWI to predict pCR accurately. This makes implementation of DWI for pCR prediction and evaluation based on one absolute ADC threshold for all breast cancer types undesirable. Multidisciplinary consensus and appropriate clinical study design, taking biological and therapeutic variation into account, is required for obtaining standardized, reliable, and reproducible DWI measurements for pCR/non-pCR identification.

Keywords: Breast cancer; DWI; Methodology; Neoadjuvant; pCR.

Fig. 1

Flow chart selection process review

Fig. 2

Mean/median ADC-values (× 10⁻³ mm²/s) in different studies pre, during and post-NST between the pCR group (left figure) and the non-pCR group (right figure). Different time points are connected by solid (: studies acquired at 1.5 T), dashed (: studies acquired at 3.0 T) lines. Hahn et al. and Partridge et al. used both 1.5 T and 3.0 T scanners represented with non-connected points. The legend shows different studies that are included in the graphs. Note: the period of a cycle of neoadjuvant therapy (number of weeks) can differ and within and between studies as well as the total number of cycles. Subsequently, the solid, and dashed arrow lines should not be used for interpolation of ADC-values between two measuring time points. For Woodhams et al. [64] only the pCR-definition from the full-text was used, ADC rounded at one decimal. For Kim et al. [53] Miller and Payne grade 4 as good responders included

Fig. 3

Studies reporting the percentage difference in ADC for pCR and non-pCR from baseline for the general study population at different time points. Note: The period of a cycle of neoadjuvant therapy (number of weeks) can differ within and between studies as well as the total number of cycles

Fig. 4

ADC-values (× 10⁻³ mm²/s) at baseline per molecular subtype for two of the included studies, with two subtypes (HR-) in a and two subtypes (HR+) in b. Bufi et al. [17] distinguished triple negative, HER2-enriched, luminal, hybrid (: luminal and HER2+, HR+/HER2+) tumors. Liu et al. [16] distinguished luminal A (ER+ and/or PR+ incl. Ki67 < 14% or HER2−), luminal B (ER+ and/or PR+ incl. Ki67 ≥ 14% or HER2+), HER2-enriched and triple negative tumors. In this graph, the types from Liu et al. [16] of luminal A are appointed as HR+/HER2− and luminal B as HR+/HER2−. From Bufi et al. [17] the luminal group is appointed as HR+/HER2−. From Pereira et al. [18] three subtypes were reported

Fig. 5

Mean/median ADC (× 10⁻³ mm²/s) at baseline for pCR and non-pCR (and if known, the standard deviation), using different sub-classifications for pCR. For Woodhams et al. [64] mean and standard deviation extracted from data supplementary material, rounded by two decimals for both pCR-definitions: with and without DCIS

Fig. 6

Schematic overview, with the semi logarithmic plots (and S0, the signal at b = 0 without perfusion component) of the signal attenuation of pure diffusion (blue curve) and signal attenuation by (micro)perfusion, diffusion and including contribution of noise by the rician noise floor (red curve). Within the red curve, the first small arrow represents the mono-exponential slope (ADC1) within segment I, the second small arrow includes the mono-exponential slope in segment II (with ADC2). The large arrow represents the mono-exponential approach/slope (ADC3) using two b-values, one in segment I and one in segment II. Three segments of diffusion sensitive gradient strength, by the b-values are defined; I: diffusion and flow-sensitive b-values (diffusion gradients); II: diffusion sensitive, flow insensitive b-values; III: flow insensitive and noise sensitive b-values. The b-value independent rician noise level is mentioned as noise floor. Note: ADC1 + ADC2 = ADC3. The axis scales, slopes and by this the numeric functions are used as a schematic representation for the general picture and therefore might differ from clinical practice