An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Ethics Approval and Consent to Participate
2.2. DNA Extraction
2.3. Exome Sequencing
2.4. Complex Analyses
2.5. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Some VUS May Respond to Olaparib
3.3. Response of VUS to Olaparib Could Be Predicted before Treatment
3.4. VUS Classification Allows one to Predict Benefit from Particular PARP Inhibitors
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
List of Abbreviations
References
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Clinical and Pathologic Characteristics | n (%) | Median Age (Min–Max), Years |
---|---|---|
Age at olaparib treatment | 41 | 63 (31–84) |
Organs | ||
Ovary | 23 (56.2%) | 63 (43–84) |
Breast | 8 (19.5%) | 62 (31–83) |
Digestive tract | 8 (19.5%) | 62 (50–76) |
(pancreas, colon, rectum) | (5, 2, 1) | |
Endometrium | 1 (2.4%) | 56 |
Skin | 1 (2.4%) | 73 |
Histology | ||
Adenocarcinoma (breast, digestive tract) | 16 (39%) | |
High-grade serous adenocarcinoma | 22 (53.8%) | |
Clear cell adenocarcinoma | 1 (2.4%) | |
Basal Cell carcinoma | 1 (2.4%) | |
Unknown | 1 (2.4%) | |
Response to platinum salts | Days (min–max) | |
Number of patients treated | 39 (92.9%) | |
Progression Free Survival | 126 (30–637) | |
PFS < 90 days | 7 (18%) | |
PFS > 90 days | 32 (82%) |
Cancer Type, Patient No. | Gene(s) | Nucleotide Variant | Protein Variant | Impact | PFS (Days) |
---|---|---|---|---|---|
Ovarian #1 | BRCA1 | c.798_799delTT | Ser267LysfsTer19 | Pathogenic | 1218 (still under olaparib) |
Ovarian #2 | BRCA1 | c.53T > C | p.Met18Thr | Unknown | 240 |
Ovarian #3 | BRCA1 | c.2477_2478delCA | p.Thr826ArgfsTer4 | Pathogenic | 953 |
Ovarian #4 | BRCA2 | c.7617 + 1G > T | Pathogenic | 441 | |
Ovarian #5 | BRCA1 | c.181T > G | p.Cys61Gly | Pathogenic | 59 |
Ovarian #6 | PALB2 | c.656A > G | p.Asp219Gly | Unknown | 224 |
Ovarian #7 | BRCA2 | c.3847_3848delGT | p.Val1283LysfsTer3 | Pathogenic | 1659 (still under olaparib) |
Ovarian #8 | BRCA1 | c.3708T > G | p.Asn1236Lys | Benign | 81 |
Ovarian #9 | BRCA1 | c.2066_2069delGTAA | p.Ser689LysfsTer11 | Pathogenic | 910 |
Ovarian #10 | BRCA1 | c.3839_3843delinsAGGC | p.Ser1280_Gln1281delinsTer | Pathogenic | 94 |
Ovarian #11 | BRCA2 | c.8504C > G | p.Ser2835Ter | Pathogenic | 1359 (still under olaparib) |
Ovarian #12 | BRCA1 | c.4956G > A | p.Met1652Ile | Benign | 58 |
BRCA2 | c.9976A > T | p.Lys3326Ter | Benign | ||
Ovarian #13 | BRCA1 | c.349C > T | p.His117Tyr | Unknown | 120 |
BRCA2 | c.8494G > T | p.Glu2832Ter | Pathogenic | ||
Ovarian #14 * | BRCA1 | c.4204C > T | p.Gln1402Ter | Pathogenic | 101 |
Ovarian #15 * | BRCA1 | c.4204C > T | p.Gln1402Ter | Pathogenic | 168 |
Ovarian #16 | BRCA1 | c.68_69delAG | p.Glu23ValfsTer17 | Pathogenic | 79 |
Ovarian #17 | BRCA2 | c.3267_3268delGA | p.Gln1089HisfsTer9 | Pathogenic | 614 |
Ovarian #18 | BRCA1 | c.191G > A | p.Cys64Tyr | Pathogenic | 636 |
Ovarian #19 | BRCA2 | c.5350_5351delAA | p.Asn1784HisfsTer2 | Pathogenic | 1 (allergic reaction) |
Ovarian #20 | BRCA1 | c.2744C > T | p.Ser915Phe | Unknown | 368 |
Ovarian #21 | BRCA2 | c.2539A > T | p. Arg847Ter | Pathogenic | 288 |
Ovarian #22 | ATM | c.103C > T | p.Arg35Ter | Pathogenic | 306 |
Ovarian #23 | BRCA2 | c.1690T > C | p.Met990Lys | Unknown | 93 |
Breast #1 | BRCA2 | c.1981_1984dup | p.Ser662Ter | Pathogenic | 231 |
Breast #2 | BRIP1 | c.2002delG | p.Glu668LysfsTer20 | Pathogenic | 98 |
Breast #3 | BRCA1 | c.5341G > T | p.Glu1781Ter | Pathogenic | 190 |
Breast #4 | BRCA2 | c.7654dupA | p.Ile2552AsnfsTer2 | Pathogenic | 223 |
BRCA2 | c.7645_7668delTGCATAAAAATTAACAGCAAAAAT | p.Cys2549_Asn2556del | Unknown | ||
Breast #5 | BRCA1 | c.4251_4252delG > T | p.Leu1418ArgfsTer9 | Pathogenic | 1212 (still under olaparib) |
Breast #6 | BRCA1 | c.2783G > T | p.Gly928Val | Unknown | 136 |
Breast #7 | BRCA1 | c.3485delA | Asp1162ValfsTer48 | Pathogenic | 116 |
Breast #8 | BRCA2 | c.4860A > T | p.Leu1620Phe | Unknown | 144 |
RAD51D | c.328G > A | p.Asp110Asn | Unknown | ||
Digestive tract #1 (colon) | PALB2 | c.2719G > A | p.Glu907Lys | Unknown | 36 |
Digestive tract #2 (pancreas) | BRCA1 | c.2521C > T | p.Arg841Trp | Unknown | 12 |
UIMC1 | c.1690T > C | p.Tyr564His | Unknown | ||
Digestive tract #3 (pancreas) | CHEK2 | c.349A > G | p.Arg160Gly | Pathogenic | 64 |
Digestive tract #4 (rectum) | BRCA1 | c.2521C > T | p. Arg841Trp | Probably Benign | 62 |
Digestive tract #5 (pancreas) | BRCA1 | c.5128A > C | p.Met1710Leu | Unknown | 54 |
Digestive tract #6 (pancreas) | BRCA1 | c.5295A > C | p.Glu1786Asp | Unknown | 12 |
Digestive tract #7 (pancreas) | BRIP1 | c.3G > A | p.Met1? | Unknown | 27 |
Digestive tract #8 (pancreas) | ATM | c.598C > T | p.Gln200Ter | Pathogenic | 20 |
Endometrium #1 | PTEN | c.867dupA | p.Val290SerfsTer8 | Pathogenic | 190 |
Skin #1 | PALB2 | c.2431C > T | p.Pro811Ser | Unknown | 210 |
RAD50 | c.3041A > G | p.Gln1014Arg | Unknown | ||
RAD51C | c.584C > T | p.Ala195Val | Unknown |
Cancer Type, Patient No. | Gene(s) | Nucleotide Variant | Protein Variant | Second Hit Prediction * | Dann Prediction | PROVEAN Prediction | P S | Final Prediction | PFS (Days) |
---|---|---|---|---|---|---|---|---|---|
Ovarian #2 | BRCA1 | c.53T > C | p.Met18Thr | B (0.19, Red) | D | D | 1 | S | 240 |
Ovarian #6 | PALB2 | c.656A > G | p.Asp219Gly | D (1.12, Green) | B | B | 1 | S | 224 |
Ovarian #20 | BRCA1 | c.2744C > T | p.Ser915Phe | B (0.14, Red) | D | D | 2 | S | 368 |
Ovarian #23 | BRCA2 | c.1690T > C | p.Met990Lys | B (0.26, Red) | B | D | 1 | S or R | 93 |
Breast #6 | BRCA1 | c.2783G > T | p.Gly928Val | D (1.04, Green) | U | D | 1 | S | 136 |
Breast #8 | BRCA2 | c.4860A > T | p.Leu1620Phe | B (0.44, Red) | B | D | 2 | S | 144 |
RAD51D | c.328G > A | p.Asp110Asn | B (0.16, Red) | D | D | ||||
Digestive tract #1 (colon) | PALB2 | c.2719G > A | p.Glu907Lys | B (0.66, Red) | B | B | 1 | R | 36 |
Digestive tract #2 (pancreas) | BRCA1 | c.2521C > T | p.Arg841Trp | D (1.48, Green) | B | D | 3 | R | 12 |
UIMC1 | c.1690T > C | p.Tyr564His | D (0.91, Green) | D | D | ||||
Digestive tract #5 (pancreas) | BRCA1 | c.5128A > C | p.Met1710Leu | B (0.34, Red) | B | B | 0 | R | 54 |
Digestive tract #6 (pancreas) | BRCA1 | c.5295A > C | p.Glu1786Asp | B (0.27, Red) | U | B | 1 | R | 12 |
Digestive tract #7 (pancreas) | BRIP1 | c.3G > A | p.Met1? | D (0.96, Green) | U | U | 3 | R | 27 |
Skin #1 | PALB2 | c.2431C > T | p.Pro811Ser | B (0.53, Red) | B | B | 1 | S | 210 |
RAD50 | c.3041A > G | p.Gln1014Arg | B (0.54, Red) | B | B | ||||
RAD51C | c.584C > T | p.Ala195Val | D (0.72, Green) | D | B |
Characteristics | Olaparib n (%) | Niraparib n (%) |
---|---|---|
Total | 14 | 24 |
Histology | ||
High grade serous adenocarninoma | 12 (86%) | 24 (100%) |
Endometrioid carcinoma | 2 (14%) | 0 |
Response to platin | ||
Complete response | 5 (36%) | 8 (33%) |
Partial response | 7 (50%) | 14 (58%) |
Stable disease | 2 (14%) | 2 (9%) |
Genes | Nucleotide Variant | Protein Variant | Second Hit Prediction | Dann Prediction | Final Prediction with PROVEAN | PS | Treatment | Final Prediction | PFS (Days) |
---|---|---|---|---|---|---|---|---|---|
INPP4B | c.1381T > C | p.Phe461Leu | D | B | N | 1 | Nira | S | 392 |
ATM | c.2578G > C | p.Asp860His | B | D | D | 1 | Nira | S | 176 |
FANCF | c.373G > A | p.Asp125Asn | B | B | B | 1 | Nira | S | 113 |
PALB2 | c.1273G > A | p.Val425Met | D | B | B | ||||
RAD51B | c.902G > A | p.Ser301Asn | B | D | B | ||||
ATM | c.4079G > A | p.Ser1360Asn | B | B | B | 1 | Nira | R | 342 |
BRCA2 | c.9109C > G | p.Gln3037Glu | U | B | B | 2 | Nira | R | 84 |
BRCA2 | c.1181A > C | p.Glu394Ala | U | B | B | 1 | Nira | R | 87 |
BRCA1 | c.1692T > A | p.Asn564Lys | B | B | B | 1 | Nira | R | 469 |
RAD50 | c.527C > T | p.Thr176Ile | U | D | B | 1 | Nira | U | 63 |
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Chevrier, S.; Richard, C.; Collot, T.; Mananet, H.; Arnould, L.; Boidot, R. An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers. Cancers 2021, 13, 3113. https://doi.org/10.3390/cancers13133113
Chevrier S, Richard C, Collot T, Mananet H, Arnould L, Boidot R. An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers. Cancers. 2021; 13(13):3113. https://doi.org/10.3390/cancers13133113
Chicago/Turabian StyleChevrier, Sandy, Corentin Richard, Thomas Collot, Hugo Mananet, Laurent Arnould, and Romain Boidot. 2021. "An Algorithm Combining Patient Performance Status, Second Hit Analysis, PROVEAN and Dann Prediction Tools Could Foretell Sensitization to PARP Inhibitors in Digestive, Skin, Ovarian and Breast Cancers" Cancers 13, no. 13: 3113. https://doi.org/10.3390/cancers13133113