Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers

Abstract

Background:Although distant metastasis (DM) in breast cancer (BC) is the most lethal form of recurrence and the most common underlying cause of cancer related deaths, the outcome following the development of DM is related to the site of metastasis. Triple negative BC (TNBC) is an aggressive form of BC characterised by early recurrences and high mortality. Athough multiple variables can be used to predict the risk of metastasis, few markers can predict the specific site of metastasis. This study aimed at identifying a biomarker signature to predict particular sites of DM in TNBC.Methods:A clinically annotated series of 322 TNBC were immunohistochemically stained with 133 biomarkers relevant to BC, to develop multibiomarker models for predicting metastasis to the bone, liver, lung and brain. Patients who experienced metastasis to each site were compared with those who did not, by gradually filtering the biomarker set via a two-tailed t-test and Cox univariate analyses. Biomarker combinations were finally ranked based on statistical significance, and evaluated in multivariable analyses.Results:Our final models were able to stratify TNBC patients into high risk groups that showed over 5, 6, 7 and 8 times higher risk of developing metastasis to the bone, liver, lung and brain, respectively, than low-risk subgroups. These models for predicting site-specific metastasis retained significance following adjustment for tumour size, patient age and chemotherapy status.Conclusions:Our novel IHC-based biomarkers signatures, when assessed in primary TNBC tumours, enable prediction of specific sites of metastasis, and potentially unravel biomarkers previously unknown in site tropism.

Risk factors for breast cancer brain metastases: a systematic review

“…Five studies reported a statistically significant multivariable association between young age and risk for BCBM with effect estimates ranging between 1.66 -2.7 [17,25,26,44,80], whilst no significant association was found in the rest of the studies considering solely HER2-positive patients, likely reflecting the small sample size used [20, 23-25, 61, 81]. Similarly, in the subset of studies involving TNBC patients, age was not found to impact BCBM [24,39,71].…”

“…In total, 69 studies were identified investigating predisposing factors for BCBM [10,12,. The majority of the included studies involved patients of all BC subtypes; thirteen reported risk factors for BM in HER2positive patients [17, 20, 23-27, 44, 47, 61, 66, 80, 81] and three in TNBC patients [24,39,71]. Twelve studies compared clinicopathological characteristics of BCBM patients that developed BM as a first site of relapse, with those who first developed metastases elsewhere [10,12,21,28,30,31,39,46,54,63,66,73].…”

“…The effect of age on the risk for BCBM progression was examined in 22 studies with unselected BC patient populations; six studies compared the mean/median age of patients with and without BM [10,21,36,52,59,70], ten studies assessed age as a di or trichotomous variable [16,19,24,33,38,50,53,57,75,78], and six assessed age as a continuous variable [29,55,63,71,72,79]. Despite the marked heterogeneity in metrics and cutoff points used, young age at primary or metastatic breast cancer (MBC) diagnosis was constantly associated with BCBM, with fourteen studies reporting a statistically significant univariate association [16,19,21,24,29,33,38,52,53,57,70,75,78,79] and eight studies a statistically significant multivariable association with effect estimates ranging between 0.97 -2.0 [21,24,29,33,38,53,55,57].…”

“…Only one study involving HER2-positive patients, reported significant multivariate association between tumor size and BCBM (>2 cm, HR:4.94) [80]. Separate analyses in a study considering solely TNBC [71] revealed increased tumor size to significantly associate with BM progression on multivariate analysis (HR:4.632, p = 0.0071).…”

“…In the past decade, a number of BCBM predictive models have been proposed on the basis of known and novel risk factors; though with variable results [29,53,71,78,102]. Table 4 provides details on the methodological aspects of these models.…”