Reports From the Journal of Clinical Oncology

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Survival in Metastatic Triple-Negative Breast Cancer Explored in Retrospective Study 

In a study reported in the Journal of Clinical Oncology, Stover et al found that cell-free (cf) DNA tumor fraction ≥ 10% was associated with worse survival in metastatic triple-negative breast cancer, and that several somatic copy number alterations are enriched and prognostic in metastatic disease. 

Viktor A. Adalsteinsson, PhD, of
the Broad Institute of Harvard and Massachusetts Institute of Technology, is the corresponding author for the Journal of
Clinical Oncology article.

Viktor A. Adalsteinsson, PhD, of the Broad Institute of Harvard and Massachusetts Institute of Technology, is the corresponding author for the Journal of Clinical Oncology article.

Study Details 

The retrospective cohort study involved 506 plasma samples from 164 patients with biopsy-proven metastatic triple-negative breast cancer at a single tertiary care institution who had received chemotherapy in the neoadjuvant/ adjuvant or metastatic setting between August 2010 and November 2016. Low-coverage genome-wide sequencing of cfDNA from plasma was performed. 

cfDNA and Somatic Copy Number Alterations 

Without prior knowledge of extant tumor mutations, cfDNA tumor fraction was determined for 96.3% of patients and somatic copy number alterations for 63.9%. 

Copy number profiles and percent genome altered were highly similar between metastatic and primary triple-negative breast cancers. Several somatic copy number alterations were more frequent in metastatic triple-negative breast cancers vs paired primary tumors and primary triple-negative breast cancers in publicly available data sets, including chromosomal gains in the drivers NOTCH2, AKT2, and AKT3. Gain/ amplification of both 18q11 and 19p13 was associated with poorer survival in metastatic disease in multivariate analysis (hazard ratio [HR] = 3.30, P = .012), as well as in primary triple-negative breast cancers. 

The prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly poorer overall survival in metastatic disease (median = 6.4 vs 15.9 months for < 10%), with the association remaining significant on multivariate analysis including clinicopathologic factors (HR = 2.14, P < .001). 

The investigators concluded, “We present the largest genomic characterization of metastatic [triple-negative breast cancer] to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic [triple-negative breast cancer] cohort. Specific [somatic copy number alterations] are enriched and prognostic in metastatic [triple-negative breast cancer], with implications for metastasis, resistance, and novel therapeutic approaches.” ■

The study was supported by the Gerstner Family Foundation, Susan G. Komen for the Cure, The Pink Agenda, Breast Cancer Research Foundation, V Foundation for Cancer Research, and National Cancer Institute grants. 

Stover DG, Parsons HA, Ha G, et al: J Clin Oncol. January 3, 2018 (early release online).


Cabozantinib vs Everolimus in Patients With Bone Metastasis From Advanced RCC 

In a subgroup analysis of the phase III METEOR trial of advanced renal cell carcinoma (RCC) patients with with bone metastases, cabozantinib was associated with improved outcomes vs everolimus. The analysis was reported by Escudier et al in the Journal of Clinical Oncology

Bernard Escudier, MD

Bernard Escudier, MD

Study Details 

In the METEOR trial, 658 patients with advanced RCC after previous vascular endothelial growth factor receptor inhibitor therapy were randomized to receive cabozantinib at 60 mg or everolimus at 10 mg daily. Among all patients, cabozantinib was associated with improved progression-free survival, overall survival, and objective response rate.

The current prespecified subgroup analysis was based on baseline bone metastasis status according to an independent radiology committee (IRC). 

Outcomes in Patients With Bone Metastases 

Among the 77 cabozantinib and 65 everolimus recipients with bone metastases at baseline, median progression-free survival was 7.4 months vs 2.7 months (hazard ratio [HR] = 0.33, 95% confidence interval [CI] = 0.21–0.51); median overall survival was 20.1 months vs 12.1 months (HR = 0.54, 95% CI = 0.34–0.84); and overall response rate according to IRC was 17% vs 0%. Skeletal-related events occurred in 23% vs 29% of patients, and bone scan response rates were 20% vs 10%. The safety profiles of cabozantinib and everolimus in patients with bone metastases were consistent with those in patients without bone metastases. 

Progression-free survival, overall survival, and overall response rate were also improved among cabozantinib recipients without bone metastases. Patients treated with cabozantinib had greater changes in bone biomarkers, including bone-specific alkaline phosphatase, the bone formation marker N-terminal propeptide of type 1 collagen, and the bone resorption marker C-terminal cross-linked telopeptides of type I collagen. 

The investigators concluded, “Cabozantinib treatment was associated with improved [progression-free survival, overall survival, and objective response rate] when compared with everolimus treatment in patients with advanced RCC and bone metastases and represents a good treatment option for these patients.” ■

Editorial support for the article was funded by Exelixis. 

Bernard Escudier, MD, of Institut Gustave Roussy, is the corresponding author for the Journal of Clinical Oncology article. 

Escudier B, Powles T, Motzer RJ, et al: J Clin Oncol. January 8, 2018 (early release online).


Passive Scattering Proton Therapy vs Intensity-Modulated Photon Radiotherapy for Locally Advanced NSCLC 

In a study reported in the Journal of Clinical Oncology, Liao et al found that passive scattering proton radiotherapy improved heart—but not lung—radiation dose-volume indices vs intensity-modulated photon radiotherapy in patients with advanced non–small cell lung cancer (NSCLC) receiving concurrent chemotherapy. Passive scattering proton radiotherapy was not associated with improved rates of radiation pneumonitis or local failure. 

Study Details 

In the trial, 149 patients with stage IIB to IIIB NSCLC (or stage IV NSCLC with a single brain metastasis, or recurrent lung or mediastinal disease after surgery) who were candidates for concurrent chemoradiation treated at The University of Texas MD Anderson Cancer Center or Massachusetts General Hospital were randomized to receive passive scattering proton radiotherapy (n = 57) or intensity-modulated radiation therapy (n = 92). The trial used adaptive randomization, in which real-time assessment of accumulated outcome data is used to detect differences between arms and adjust the ratio of patient allocation; thus, more patients are allocated to the better treatment plan if a difference is observed, with the allocation ratio approaching 1:1 in the absence of any difference. The primary endpoints were grade ≥ 3 radiation pneumonitis and local failure. 

Radiation Exposure 

The study assessed measurements based on the concept of relative biologic effectiveness, which is the ratio of biologic effectiveness of one type of ionizing radiation relative to another, given the same amount of absorbed energy. Overall, there were no differences between groups in mean dose in Gy(RBE)—ie, the absorbed Gy dose multiplied by the RBE factor for protons—in the lung (P = .818) or esophagus (P = .717). Passive scattering proton radiotherapy exposed less lung tissue to radiation doses of 5 to 10 Gy (relative biologic effectiveness), more lung tissue to ≥ 20 Gy (relative biologic effectiveness), and less heart tissue at all dose levels from 5 to 80 Gy (RBE) (P = .002). 

For the passive scattering proton radiotherapy vs intensity-modulated photon radiotherapy groups, 1-year rates of grade ≥ 3 radiation pneumonitis were 10.5% vs 6.5% (P = .537) and local failure rates were 10.5% vs 10.9% (P = 1.0). Exploratory analysis comparing 12-month combined radiation pneumonitis and local failure rates for patients enrolled before vs after the trial midpoint showed improvements with later enrollment in both the passive scattering proton radiotherapy group (31.0% vs 13.1%, P = .027) and the IMRT group (21.1% vs 18.2%, P = .047). 

The investigators concluded, “[Passive scattering proton radiotherapy] did not improve dose-volume indices for lung, but did for heart. No benefit was noted in [radiation pneumonitis] or [local failure] after [passive scattering proton radiotherapy]. Improvements in both endpoints were observed over the course of the trial.” ■

The study was supported by National Cancer Institute grants. 

Liao Z, Lee JJ, Komaki R, et al. J Clin Oncol. January 2, 2018 (early release online).