Table 2.
OncoKB database and gene actionability
| Tumour type: breast cancer | ||||||
|---|---|---|---|---|---|---|
| Level | Alteration: oncogenic mutations | No of mutations (%) | Drugs | Citations | ||
| BC (N = 32) | BM (N = 32) | |||||
| 1 | PIK3CA | 10 (15) | 10 (17) | Alpelisib + Fulvestrant | 3 | PI3K inhibition results in enhanced oestrogen receptor function and dependence in hormone receptor-positive breast cancer. Bosch A et al. Sci Transl Med. 2015 PMID: 25,877,889 |
| Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Oestrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. Juric D et al. JAMA Oncol. 2019 PMID: 30,543,347 | ||||||
| Alpelisib for PIK3CA -Mutated, Hormone Receptor-Positive Advanced Breast Cancer. André F et al. N Engl J Med. 2019 PMID: 31,091,374 | ||||||
| 3 | GDC-0077 | 3 | 355TiP Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P) + fulvestrant (F) in patients (pts) with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR + /HER2– LA/MBC). TurnerN et al. Annals Onc. 2020 10.1016/j.annonc.2020.08.457 | |||
| Juric D et al. Abstract# OT1-08–04, SABCS 2019 | ||||||
| Hong R et al. Abstract# PD4-14, SABCS 2017 | ||||||
| 3 | Copanlisib + Fulvestrant | 7 | First-in-human phase I study of copanlisib (BAY 80–6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumours and non-Hodgkin's lymphomas. Patnaik A et al. Ann Oncol. 2016 PMID: 27,672,108 | |||
| Exceptional Response to Copanlisib in a Heavily Pretreated Patient With PIK3CA-Mutated Metastatic Breast Cancer. Spathas N et al. JCO Prec Onc. 2020 10.1200/PO.19.00049 | ||||||
| Staben et al. Abstract# DDT02-01, AACR 2017 | ||||||
| De et al. Abstract# 3438, AACR 2019 | ||||||
| O'Brien, NA et al. Abstract P3-04–15. Cancer Research, 2017 | ||||||
| De et al. Abstract# P2-03–08, SABCS 2018 | ||||||
| Edgar et al. Abstract# 156, AACR 2017 | ||||||
| 3 | AKT1 | 12 (18) | 12 (20.3) | AZD5363 | 4 | Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumour activity, and correlation of monotherapy activity with genetic background. Davies BR et al. Mol Cancer Ther. 2012 PMID: 22,294,718 |
| Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. Addie M et al. J Med Chem. 2013 PMID: 23,394,218 | ||||||
| AKT Inhibition in Solid Tumours With AKT1 Mutations. Hyman DM et al. J Clin Oncol. 2017 PMID: 28,489,509 | ||||||
| Tumours with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors. Davies BR et al. Mol Cancer Ther. 2015PMID: 26,351,323 | ||||||
| 1 | ERBB2/HER2 | 1 (1.5) | 1 (1.7) | Neratinib | 3 | Activating HER2 mutations in HER2 gene amplification negative breast cancer. Bose R et al. Cancer Discov. 2013 PMID: 23,220,880 |
| The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Minami Y et al. Oncogene. 2007 PMID: 17,311,002 | ||||||
| HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Hyman DM et al. Nature. 2018 PMID: 29,420,467 | ||||||
| 3 | ESR1 | 13 (19.4) | 11 (18.6) | AZD9496 | 2 | Efficacy of a novel orally active SERD AZD9496 against hormone dependent post-menopausal breast cancer depends on inhibition of cellular aromatase activity. Kazi A et al. J Ster Biochem Mol Biol. 2020 ISSN: 0960–0760 |
| A Randomised, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in patients with Newly Diagnosed ER + HER2 − Primary Breast Cancer. Robertson JFR et al. 2020 PMID: 32,234,755 | ||||||
| 1 | Abemaciclib + Fulvestrant | 4 | Analysis of Overall Survival Benefit of Abemaciclib Plus Fulvestrant in Hormone Receptor–Positive, ERBB2-Negative Breast Cancer. Gil-Sierra MD et al. JAMA Oncol. 2020 10.1001/jamaoncol.2020.1516 | |||
| The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomised Clinical Trial. Sledge GW Jr et al. JAMA Oncol. 2019 PMID: 31,563,959 | ||||||
| Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists. Toy W et al. Cancer Discov. 2017 PMID: 27,986,707 | ||||||
| Plasma ESR1 Mutations and the Treatment of Oestrogen Receptor-Positive Advanced Breast Cancer. Fribbens C et al. J Clin Oncol. 2016 PMID: 27,269,946 | ||||||
| NA | TP53 | 31 (46.3) | 25 (42.4) | |||
| Total no of mutations | 67 | 59 | ||||
A search on the oncoKB for the actionability of PIK3CA, AKT1, ESR1, ERBB2/HER2 and TP53 oncogenic mutations on breast cancer identified 7 protocols. 1. FDA-approval, 3. Clinical evidence
NA Not available