Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial

Abstract

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme‐linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease‐free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2‐negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5‐year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT‐B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5‐year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5‐year DFS for patients with high sCAIX (81 vs. 73.6 months, log‐rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.

Both p53 codon 72 Arg/Arg and pro/Arg genotypes in glioblastoma multiforme are associated with a better prognosis in bevacizumab treatment

“…These biomarkers usually are not only expressed abnormally but are involved in the vital biological processes, including angiogenesis, differentiation, and growth [55]. Several predictive genomic biomarkers for bevacizumab have been identified in various indications, including pH-weighted amine chemical exchange saturation transfer echoplanar imaging [56], soluble carbonic anhydrase IX [57], and apelin/APLN [58], among others, while none has been prospectively validated yet [59]. The lack of any ability to identify patients who will benefit a priori, that is, the absence of a predictive biomarker, means that nearly every patient is treated with the antibody, in spite of not knowing which patients would be more likely to derive any benefit from it.…”

Harnessing Induced Essentiality: Targeting Carbonic Anhydrase IX and Angiogenesis Reduces Lung Metastasis of Triple Negative Breast Cancer Xenografts

“…Indeed, studies have shown that genetic depletion of CAIX expression enhances the efficacy of bevacizumab in preclinical tumor models [29]. Furthermore, recent evaluation of soluble CAIX (sCAIX) induced by shedding in breast cancer patients treated with bevacizumab showed that sCAIX levels are predictive of therapeutic response to inhibition of angiogenesis [30]. However, the impact of targeting CAIX activity in combination with anti-angiogenic agents in a therapeutically relevant manner in breast cancer has not been evaluated.…”

How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH

“…CAIX can also be detected in tumour stroma, which is associated with poor prognosis [152]. As a consequence of ectodomain shedding and release in exosomes, CAIX can be detected in the body fluids of cancer patients, and this can be exploited for non-invasive screening or monitoring tumour response to therapy [153,154].…”