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Multicenter Study
. 2015 Nov 1;93(3):631-8.
doi: 10.1016/j.ijrobp.2015.06.021. Epub 2015 Jun 25.

Integration of a Radiosensitivity Molecular Signature Into the Assessment of Local Recurrence Risk in Breast Cancer

Javier F Torres-Roca  1 , William J Fulp  2 , Jimmy J Caudell  3 , Nicolas Servant  4 , Marc A Bollet  5 , Marc van de Vijver  6 , Arash O Naghavi  3 , Eleanor E Harris  7 , Steven A Eschrich  8
Affiliations
Multicenter Study

Integration of a Radiosensitivity Molecular Signature Into the Assessment of Local Recurrence Risk in Breast Cancer

Javier F Torres-Roca et al. Int J Radiat Oncol Biol Phys. .

Abstract

Purpose: Recently, we developed radiosensitivity (RSI), a clinically validated molecular signature that estimates tumor radiosensitivity. In the present study, we tested whether integrating RSI with the molecular subtype refines the classification of local recurrence (LR) risk in breast cancer.

Methods and materials: RSI and molecular subtype were evaluated in 343 patients treated with breast-conserving therapy that included whole-breast radiation therapy with or without a tumor bed boost (dose range 45-72 Gy). The follow-up period for patients without recurrence was 10 years. The clinical endpoint was LR-free survival.

Results: Although RSI did not uniformly predict for LR across the entire cohort, combining RSI and the molecular subtype identified a subpopulation with an increased risk of LR: triple negative (TN) and radioresistant (reference TN-radioresistant, hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.15-0.92, P=.02). TN patients who were RSI-sensitive/intermediate had LR rates similar to those of luminal (LUM) patients (HR 0.86, 95% CI 0.47-1.57, P=.63). On multivariate analysis, combined RSI and molecular subtype (P=.004) and age (P=.001) were the most significant predictors of LR. In contrast, integrating RSI into the LUM subtype did not identify additional risk groups. We hypothesized that radiation dose escalation was affecting radioresistance in the LUM subtype and serving as a confounder. An increased radiation dose decreased LR only in the luminal-resistant (LUM-R) subset (HR 0.23, 95% CI 0.05-0.98, P=.03). On multivariate analysis, the radiation dose was an independent variable only in the LUMA/B-RR subset (HR 0.025, 95% CI 0.001-0.946, P=.046), along with age (P=.008), T stage (P=.004), and chemotherapy (P=.008).

Conclusions: The combined molecular subtype-RSI identified a novel molecular subpopulation (TN and radioresistant) with an increased risk of LR after breast-conserving therapy. We propose that the combination of RSI and molecular subtype could be useful in guiding radiation therapy-based decisions in breast cancer.

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Figures

Figure 1
Figure 1
Integrating RSI subtype with breast molecular phenotypes refines the genomic classification of breast cancer. (A) Local recurrece risk for RSI S/Int vs RSI-R in all (B) ER-positive and (C) ER-negative patients. (D) Local recurrence risk as a function of breast mlecular subtype. (E) Local recurrence risk combining breast molecular subtype and RSI
Figure 2
Figure 2
Integration of RSI and molecular subtypes identifies a small sub-population that benefits from RT- dose escalation. (A)Local recurrence rates for all luminal patients are shown comparing patients treated 66 Gy or less (black) or more than 66 Gy (red). (B-D) Recurrence rates in luminal patients by RSI subtype. RT dose has no overall impact on local recurrence of luminal patients that are RSI-S (A) or RSI-Int (B). However, higher RT dose reduces the risk of local recurrence for RSI-R patients (D)(p=0.02)
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Comment in

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