18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial

Abstract

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18 F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-ofopportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/ changes.Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB ¼ 3 (P ¼ 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P ¼ 0.09). In Arm B, 18F-FMISO-PET lacked predictive/ prognostic value.Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib.

Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges

“…Later studies revealed that cediranib transiently increases perfusion and oxygenation in the subset of glioblastoma patients that survive longer (31–33). Similar findings of increased vessel function and oxygenation associating with pathological response and outcome have been reported with nintedanib (34), eribulin (35), and bevacizumab (35–38) in breast cancer (BC) patients. While perfusion was reduced by bevacizumab in the overall patient cohort of non-small-cell lung cancer (NSCLC) patients, increased perfusion after bevacizumab treatment was associated with improved overall survival (39).…”

Intracellular hypoxia measured by 18F-fluoromisonidazole positron emission tomography has prognostic impact in patients with estrogen receptor-positive breast cancer

“…The clinical application of hypoxia imaging has provided essential information on tumor microenvironmental biology, adding to information on tumor size, growth factor receptors, and cellular proliferation. Hypoxia imaging may enable tailoring therapeutic strategies based on baseline risk assessment [ 26 – 29 ].…”

Validation of Residual Cancer Burden as Prognostic Factor for Breast Cancer Patients After Neoadjuvant Therapy

“…So far, the RCB score has only been used to a limited extent by independent researchers outside of the MD Anderson Cancer Center. 15,27,[33][34][35][36] In the following study, we investigated the prognostic impact of the RCB score with special emphasis on RFS in a breast cancer collective treated at a single oncology unit and analyzed at a single pathology department.…”