Assessing Prognostic and Predictive Biomarkers of Regorafenib Response in Patients with Advanced Soft Tissue Sarcoma: REGOSARC Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methods
2.1. Study Design
2.2. Translational Research
2.3. Statistical Analysis
3. Results
3.1. Patient Disposition and Disease Characteristics
3.2. Biomarker Distribution
3.3. Survival Outcomes
3.4. Evaluation of the Prognostic Value of Biomarkers
3.5. Evaluation of the Predictive Value of Biomarkers
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
References
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Characteristics | Regorafenib n = 71 | Placebo n = 63 | Total n = 134 | ||||
---|---|---|---|---|---|---|---|
Sex | Male | 32 | 45% | 31 | 49% | 63 | 47% |
Female | 39 | 55% | 32 | 51% | 71 | 53% | |
Country | France | 64 | 90% | 58 | 92% | 122 | 91% |
Austria | 7 | 10% | 5 | 8% | 12 | 9% | |
ECOG PS | 0 | 33 | 46% | 29 | 46% | 62 | 46% |
1 | 38 | 54% | 33 | 52% | 71 | 53% | |
2 | 0 | 0% | 1 | 2% | 1 | 1% | |
Age | Median (range) | 59 | (21–81) | 59 | (22–80) | 59 | (21–81) |
Histology | Liposarcoma (Cohort A) | 18 | 25% | 20 | 32% | 38 | 28% |
Leiomyosarcoma (Cohort B) | 23 | 32% | 22 | 35% | 45 | 34% | |
Synovial sarcoma (Cohort C) | 10 | 14% | 7 | 11% | 17 | 13% | |
Other sarcomas (Cohort D) * | 20 | 28% | 14 | 22% | 34 | 25% | |
Tumor grade (FNCLCC) | Grade 1 | 7 | 10% | 4 | 6% | 11 | 8% |
Grade 2 | 18 | 25% | 35 | 56% | 53 | 40% | |
Grade 3 | 34 | 48% | 17 | 27% | 51 | 38% | |
Not documented | 12 | 17% | 7 | 11% | 19 | 14% | |
Primary site | Retroperitoneal | 24 | 34% | 24 | 38% | 48 | 36% |
Lower limb | 19 | 27% | 18 | 29% | 37 | 28% | |
Uterus | 10 | 14% | 7 | 11% | 17 | 13% | |
Trunk | 8 | 11% | 3 | 5% | 11 | 8% | |
Viscera | 3 | 4% | 6 | 10% | 9 | 7% | |
Upper limb | 1 | 1% | 3 | 5% | 4 | 3% | |
Head and neck | 4 | 6% | 0 | 0% | 4 | 3% | |
Other | 2 | 3% | 2 | 3% | 4 | 3% | |
Staging | Metastatic disease | 69 | 97% | 61 | 97% | 130 | 97% |
Metastatic sites ** | |||||||
Lung | 46 | 65% | 48 | 76% | 94 | 70% | |
Other | 30 | 42% | 31 | 49% | 61 | 46% | |
Peritoneal | 24 | 34% | 18 | 29% | 42 | 31% | |
Liver | 21 | 30% | 20 | 32% | 41 | 31% | |
Lymph nodes | 19 | 27% | 12 | 19% | 31 | 23% | |
Bones | 11 | 15% | 13 | 21% | 24 | 18% | |
Cutaneous | 6 | 8% | 6 | 10% | 12 | 9% | |
Pleural | 5 | 7% | 5 | 8% | 10 | 7% | |
Prior treatments | Prior surgery | 68 | 96% | 59 | 94% | 127 | 95% |
Prior radiotherapy | 35 | 49% | 38 | 60% | 73 | 54% | |
Prior chemotherapy | 71 | 100% | 63 | 100% | 134 | 100% | |
Number of prior chemotherapy lines (neoadjuvant, adjuvant and advanced) | Median (range) | 2 | (1–4) | 2 | (1–9) | 2 | (1–9) |
1 | 24 | 34% | 19 | 30% | 43 | 32% | |
2 | 25 | 35% | 24 | 38% | 49 | 37% | |
3 | 20 | 28% | 14 | 22% | 34 | 25% | |
4 | 2 | 3% | 5 | 8% | 7 | 5% | |
9 | 0 | 0% | 1 | 2% | 1 | 1% | |
Prior treatments (≥10% of patients) *** | Doxorubicin | 71 | 100% | 60 | 95% | 131 | 98% |
Ifosfamide | 41 | 58% | 37 | 59% | 78 | 58% | |
Trabectedin | 30 | 42% | 23 | 37% | 53 | 40% | |
Gemcitabine | 9 | 13% | 18 | 29% | 27 | 20% | |
Dacarbazine | 6 | 8% | 14 | 22% | 20 | 15% |
Gene | Assessment Technique | Overall N = 134 | Lipo-Sarcoma N = 38 | Leiomyo-Sarcoma N = 45 | Synovial Sarcoma N = 17 | Others N = 34 | p |
---|---|---|---|---|---|---|---|
TP53 | HotSpot + FCS (1) | 35 (26%) | 5 | 16 | 1 | 13 | 0.009 |
Angiogenesis pool (2) | 20 (15%) | 7 | 5 | 1 | 7 | 0.42 | |
H19 | RNA in situ hybridization on TMA | 24 (18%) | 9 | 5 | 7 | 3 | 0.02 |
Outcome | Prognostic Value (1) | Predictive Value (2) | |||
---|---|---|---|---|---|
Gene | HR (Abnormal vs. normal) | P | HR (Rego. vs. plac.) if abnormal | HR (Rego. vs. plac.)if normal | p interaction test |
Progression-free survival | |||||
H19 | 1.41 (0.90–2.20) | 0.14 | 0.46 (0.20–1.03) | 0.46 (0.30–0.68) | 1.00 |
TP53 | 1.08 (0.72–1.60) | 0.72 | 0.40 (0.20–0.80) | 0.48 (0.32–0.74) | 0.64 |
Angiogenesis pool | 0.96 (0.59–1.57) | 0.88 | 0.52 (0.21–1.31) | 0.45 (0.31–0.67) | 0.79 |
Overall survival | |||||
H19 | 1.60 (0.96–2.68) | 0.07 | 1.00 (0.40–2.53) | 0.82 (0.51–1.32) | 0.71 |
TP53 | 1.03 (0.64–1.65) | 0.89 | 0.67 (0.30–1.49) | 0.92 (0.56–1.52) | 0.51 |
Angiogenesis pool | 0.73 (0.39–1.38) | 0.33 | 0.83 (0.53–1.31) | 1.07 (0.31–3.66) | 0.71 |
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Brodowicz, T.; Liegl-Atzwanger, B.; Penel, N.; Mir, O.; Blay, J.-Y.; Kashofer, K.; Le Cesne, A.; Decoupigny, E.; Wallet, J.; Hamacher, R.; et al. Assessing Prognostic and Predictive Biomarkers of Regorafenib Response in Patients with Advanced Soft Tissue Sarcoma: REGOSARC Study. Cancers 2020, 12, 3746. https://doi.org/10.3390/cancers12123746
Brodowicz T, Liegl-Atzwanger B, Penel N, Mir O, Blay J-Y, Kashofer K, Le Cesne A, Decoupigny E, Wallet J, Hamacher R, et al. Assessing Prognostic and Predictive Biomarkers of Regorafenib Response in Patients with Advanced Soft Tissue Sarcoma: REGOSARC Study. Cancers. 2020; 12(12):3746. https://doi.org/10.3390/cancers12123746
Chicago/Turabian StyleBrodowicz, Thomas, Bernadette Liegl-Atzwanger, Nicolas Penel, Olivier Mir, Jean-Yves Blay, Karl Kashofer, Axel Le Cesne, Emilie Decoupigny, Jennifer Wallet, Rainer Hamacher, and et al. 2020. "Assessing Prognostic and Predictive Biomarkers of Regorafenib Response in Patients with Advanced Soft Tissue Sarcoma: REGOSARC Study" Cancers 12, no. 12: 3746. https://doi.org/10.3390/cancers12123746