Fibroblast Growth Factor Receptor 2 Isoforms Detected via Novel RNA ISH as Predictive Biomarkers for Progestin Therapy in Atypical Hyperplasia and Low-Grade Endometrial Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Patient Cohort Characteristics and Treatment Outcomes
2.2. Association of FGFR2 Isoforms with Treatment Outcome
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Tissue Microarray (TMA) Construction
4.3. Immunohistochemistry Staining
4.4. BaseScope RNA ISH Assay for Detection of FGFR2 Isoforms and Signal Scoring
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinicopathologic Characteristics | Responders | Non-Responders | p-Value a | |||
---|---|---|---|---|---|---|
n = 30 | % | n = 39 | % | |||
Age Category * | <50 | 13 | 43% | 7 | 18% | 0.068 |
50–60 | 8 | 27% | 18 | 46% | ||
≥60 | 9 | 30% | 14 | 36% | ||
BMI Category* | <30 | 0 | 0% | 4 | 10% | 0.227 |
30–40 | 6 | 20% | 5 | 13% | ||
≥40 | 21 | 70% | 28 | 72% | ||
Unknown b | 3 | 10% | 2 | 5% | ||
Indication of treatment* | Comorbidities/surgical risk | 12 | 40% | 24 | 62% | 0.36 |
Patient choice | 3 | 10% | 1 | 3% | ||
Preserve fertility | 6 | 20% | 4 | 10% | ||
Symptom control until definite hysterectomy | 8 | 27% | 9 | 23% | ||
Unknown | 1 | 3% | 1 | 2.6% | ||
Hysterectomy status | No | 20 | 67% | 11 | 28% | 0.001 |
Yes | 10 | 33% | 28 | 71% | ||
Biopsy type during response assessment* | Curette | 19 | 63% | 27 | 69% | 0.466 |
Hysterectomy | 3 | 10% | 6 | 16% | ||
Pipelle | 8 | 27% | 6 | 16% | ||
Pre-treatment diagnosis* | AH | 23 | 77% | 13 | 33% | 0.0001 |
Endometrioid EC | 7 | 23% | 26 | 67% | ||
Grade | Not applicable c | 23 | 77% | 13 | 33% | 0.0001 |
Grade 1 | 5 | 17% | 24 | 62% | ||
Grade 2 | 2 | 7% | 2 | 5% | ||
FGFR2 IHC Score | Low | 5 | 17% | 8 | 21% | 0.378 |
High | 21 | 70% | 26 | 67% | ||
Missing cores b | 4 | 13% | 5 | 13% | ||
FGFR2 Isoform status* | FGFR2b+/FGFR2c− | 23 | 77% | 17 | 44% | 0.005 |
FGFR2b−/FGFR2c− | 2 | 8% | 7 | 18% | ||
FGFR2b+/FGFR2c+ | 1 | 3% | 9 | 23% | ||
Unknown | 4 | 13% | 6 | 15% | ||
Stroma1 PR Score | ≤10% | 11 | 37% | 21 | 54% | 0.049 |
>10% | 15 | 50% | 13 | 33% | ||
Missing cores b | 4 | 13 | 5 | 13% | ||
Epithelial Tumour PR Score | ≤50% | 1 | 3% | 3 | 8% | 0.42 |
>50% | 28 | 93.4% | 33 | 85% | ||
Missing cores b | 1 | 3.3% | 3 | 8% | ||
Concurrent Metformin | LNG-IUD | 23 | 77% | 25 | 64% | 0.403 |
LNG-IUD + Metformin | 7 | 23% | 13 | 33% | ||
Unknown b | 0 | 0% | 1 | 3% | ||
Route of progestin therapy | LNG-IUD only | 25 | 83% | 32 | 82% | 0.93 |
LNG-IUD + Oral Progestin | 5 | 17% | 7 | 18% |
Variables [Reference] | Univariable Analyses | Multivariable Analyses | |||||
---|---|---|---|---|---|---|---|
N Total | HR | 95%CI | LRTP | HR | 95%CI | LRTP | |
Age in years | 69 | 0.028 | 0.188 | ||||
Age 50–60 [<50] | 2.67 | 1.163–6.137 | 0.021 | 1.02 | 0.99–2.09 | 0.435 | |
Age ≥ 60 [<50] | 3.19 | 1.319–7.726 | 0.01 | 1.45 | 0872–2.65 | 0.165 | |
BMI 30 (Kg/m2) | 64 | 0.001 | 0.052 | ||||
BMI 30–40 [<30] | 1.32 | 1.15–2.452 | 0.002 | 1.13 | 0.84–1.63 | 0.056 | |
BMI ≥ 40 [<30] | 1.17 | 1.61–3.444 | 0.001 | 1.37 | 0.87–1.81 | 0.29 | |
Pre-treatment diagnosis EEC [AH] | 69 | 2.01 | 1.039–3.836 | 0.038 | 1.24 | 0.984 -2.88 | 0.078 |
Grade at diagnosis | 69 | 0.052 | 0.232 | ||||
Grade 1 [AH] | 1.98 | 1.023–3.834 | 0.043 | 1.61 | 0.86–3.01 | 0.14 | |
Grade 2 [AH] | 2.24 | 0.499–10.078 | 0.292 | 1.54 | 0.987–5.3 | 0.097 | |
FGFR2b+/FGFR2c+ [FGFR2b+/FGFR2c- a] | 50 * | 5.08 | 2.018–12.774 | 0.0001 | 4.50 | 1.92–11.32 | 0.002 |
FGFR2 protein H-Score High [Low] | 60 | 0.83 | 0.406–1.684 | 0.6 | - | - | - |
PR tumour expression ≥50% [<50%] | 63 | 0.78 | 0.245–1.367 | 0.121 | - | - | - |
PR Stromal expression ≥10% [<10%] | 63 | 0.69 | 0.346–1.356 | 0.278 | - | - | - |
LNG-IUD+ Metformin [LNG-IUD only] | 62 | 0.97 | 0.467–1.772 | 0.78 | - | - | - |
LNG_IUD +oral progestin [LNG_IUD only] | 68 | 0.61 | 0.268–1.387 | 0.238 | - | - | - |
Clinicopathologic Characteristics | FGFR2b+ /FGFR2c- | FGFR2b-/ FGFR2c- | FGFR2b+ /FGFR2c+ | Unknown Status | |||||
---|---|---|---|---|---|---|---|---|---|
n | % | n | % | n | % | n | % | ||
Age in years | <50 | 13 | 28% | 4 | 31% | 3 | 25% | 7 | 41% |
50–60 | 15 | 32% | 7 | 54% | 4 | 33% | 6 | 35% | |
>60 | 19 | 40% | 2 | 15% | 5 | 42% | 4 | 24% | |
BMI in Kg/m2 | <30 | 3 | 6% | 2 | 15% | 2 | 16.7% | 0 | 0% |
30–40 | 6 | 13% | 1 | 8% | 3 | 25% | 6 | 35% | |
>40 | 33 | 70% | 9 | 69% | 6 | 50% | 10 | 59% | |
Missing | 5 | 11% | 1 | 8% | 1 | 8% | 1 | 6% | |
Histologic diagnosis | AH | 27 | 57% | 4 | 31% | 4 | 33% | 5 | 29% |
Endometrioid EC | 20 | 43% | 9 | 69% | 8 | 67% | 12 | 71% | |
FGFR2 IHC Score | Low | 9 | 19% | 6 | 46% | 2 | 17% | 0 | 0% |
High | 36 | 77% | 7 | 54% | 10 | 83% | 4 | 23.5% | |
missing | 2 | 4% | 0 | 0% | 0 | 0% | 13 | 77% | |
PR score stroma1 | ≤10 | 23 | 49% | 8 | 62% | 8 | 67% | 3 | 19% |
>10 | 19 | 40% | 4 | 31% | 4 | 33% | 6 | 36% | |
Missing | 5 | 11% | 1 | 8% | 0 | 0% | 7 | 44% | |
Tumour PR Score | ≤50% | 3 | 6% | 2 | 15% | 1 | 8% | 1 | 6% |
>50% | 41 | 87% | 11 | 85% | 11 | 92% | 10 | 59% | |
missing | 3 | 6% | 0 | 0% | 0 | 0% | 6 | 35% | |
Combination treatment | LNG-IUD only | 30 | 71% | 10 | 77% | 7 | 64% | 9 | 56% |
LNG-IUD + Metformin | 12 | 29% | 3 | 23% | 4 | 36% | 7 | 44% | |
Missing | 0 | 0% | 0 | 0% | 0 | 0% | 0 | 0% | |
Route of treatment | LNG-IUD only | 40 | 84% | 11 | 85% | 11 | 92% | 14 | 82% |
LNG-IUD + Oral Progestin | 7 | 16% | 2 | 15% | 1 | 8% | 0 | 0% | |
Unknown | 0 | 0% | 0 | 0% | 0 | 0% | 3 | 18% | |
Treatment Outcome | Responders | 23 | 49% | 2 | 15% | 1 | 8% | 4 | 24% |
Non-responders | 17 | 36% | 7 | 54% | 9 | 75% | 6 | 35% | |
Excluded from analyses | 7 | 15% | 4 | 31% | 2 | 17% | 7 | 41% | |
Recurrence | No | 31 | 64% | 9 | 69% | 9 | 75% | 10 | 59% |
Yes | 9 | 21% | 0 | 0% | 1 | 8% | 0 | 0% | |
Excluded from analyses | 7 | 15% | 4 | 30.8% | 2 | 17% | 7 | 41% |
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Sengal, A.T.; Smith, D.; Rogers, R.; Snell, C.E.; Williams, E.D.; Pollock, P.M. Fibroblast Growth Factor Receptor 2 Isoforms Detected via Novel RNA ISH as Predictive Biomarkers for Progestin Therapy in Atypical Hyperplasia and Low-Grade Endometrial Cancer. Cancers 2021, 13, 1703. https://doi.org/10.3390/cancers13071703
Sengal AT, Smith D, Rogers R, Snell CE, Williams ED, Pollock PM. Fibroblast Growth Factor Receptor 2 Isoforms Detected via Novel RNA ISH as Predictive Biomarkers for Progestin Therapy in Atypical Hyperplasia and Low-Grade Endometrial Cancer. Cancers. 2021; 13(7):1703. https://doi.org/10.3390/cancers13071703
Chicago/Turabian StyleSengal, Asmerom T., Deborah Smith, Rebecca Rogers, Cameron E. Snell, Elizabeth D. Williams, and Pamela M. Pollock. 2021. "Fibroblast Growth Factor Receptor 2 Isoforms Detected via Novel RNA ISH as Predictive Biomarkers for Progestin Therapy in Atypical Hyperplasia and Low-Grade Endometrial Cancer" Cancers 13, no. 7: 1703. https://doi.org/10.3390/cancers13071703