|
CDKN2A del
|
high grade glioma
|
sensitive
|
Abemaciclib
|
Preclinical - Cell line xenograft |
Actionable |
In a preclinical study, Verzenio (abemaciclib) inhibited viability and G1/S transition in glioma cell lines harboring IDH1 R132H and deletion of CDKN2A in culture and inhibited tumor growth and improved survival in cell line xenograft models (PMID: 38718141).
|
38718141
|
|
CDKN2A del
|
glioblastoma
|
sensitive
|
Palbociclib
|
Preclinical - Pdx & cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) inhibited proliferation of patient-derived glioblastoma cells harboring homozygous deletion of CDKN2A in culture and prolonged survival in patient-derived xenograft models (PMID: 22711607).
|
22711607
|
|
CDKN2A del
|
high grade glioma
|
sensitive
|
Palbociclib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) inhibited viability in glioma cell lines harboring IDH1 R132H and deletion of CDKN2A in culture (PMID: 38718141).
|
38718141
|
|
CDKN2A del
|
gastrointestinal stromal tumor
|
no benefit
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial, Ibrance (palbociclib) treatment did not demonstrated clinical efficacy in heavily pre-treated gastrointestinal stromal tumor patients harboring CDKN2A homozygous or heterozygous deletion, with 86.4% (19/22) of patients demonstrated progressive disease at 4 months (PMID: 30979737; NCT01907607).
|
30979737
|
|
CDKN2A del
|
glioblastoma
|
no benefit
|
Abemaciclib + Temozolomide
|
Phase II |
Actionable |
In a Phase II trial (INSIGhT), concurrent radiation and Temodar (temozolomide) followed by adjuvant Verzenio (abemaciclib) (n=73) improved progression-free survival (PFS; HR 0.72, p=0.046) but not overall survival (OS; HR 0.69, p=0.053) compared to standard chemoradiation (n=51) in newly-diagnosed MGMT-unmethylated glioblastoma patients, PFS (HR 0.69, p=0.053) and OS (HR 0.76, p=0.12) were not improved in the CDK biomarker-positive (CDK4/6 amp or CDKN2A deletion) subgroup (PMID: 37722087; NCT02977780).
|
37722087
|
|
CDKN2A del
|
lung cancer
|
predicted - sensitive
|
PF-00477736 + PF3644022
|
Preclinical - Cell line xenograft |
Actionable |
In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of CDKN2A-deleted lung cancer (PMID: 26140595).
|
26140595
|
|
CDKN2A del
|
melanoma
|
decreased response
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, treatment with an immune checkpoint inhibitor resulted in a decreased response in melanoma patients with homozygous deletion of CDKN2A or loss of function CDKN2A mutations compared to patients with wild-type CDKN2A in one cohort, with a lower overall survival (OS) of 27.2 mo vs not yet reached and time to treatment failure of 10 vs 20.1 mo, respectively, but in a second cohort, there were no significant differences in OS (PMID: 34074656).
|
34074656
|
|
CDKN2A del
|
lung non-small cell carcinoma
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in two cohorts of non-small cell lung cancer patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors (PMID: 34074656).
|
34074656
|
|
CDKN2A del
|
bladder urothelial carcinoma
|
decreased response
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, treatment with an immune checkpoint inhibitor resulted in a decreased response in urothelial carcinoma patients with either homozygous deletion of CDKN2A or loss of function CDKN2A mutations compared to those patients with wild-type CDKN2A in two different cohorts, with an overall survival for each cohort of 8.8 and 11 mo. versus 25.2 and 19 mo, respectively, and time to treatment failure of 4.2 mo. versus 8.4 mo., respectively, in one cohort (PMID: 34074656).
|
34074656
|
|
CDKN2A del
|
renal cell carcinoma
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in one cohort of renal cell carcinoma patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors, but in another cohort were significantly associated with reduced overall survival compared to wild-type CDKN2A (13 months vs 50 months, P=0.002)(PMID: 34074656).
|
34074656
|
|
CDKN2A del
|
head and neck squamous cell carcinoma
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in two cohorts of head and neck squamous cell carcinoma patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors (PMID: 34074656).
|
34074656
|
|
CDKN2A del
|
gastroesophageal cancer
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in one cohort of esophagogastric cancer patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors, but in another cohort were significantly associated with reduced overall survival compared to wild-type CDKN2A (8 months vs 17 months, P=0.006) (PMID: 34074656).
|
34074656
|
|
CDKN2A del RB1 pos
|
glioblastoma
|
predicted - sensitive
|
Ribociclib
|
Phase 0 |
Actionable |
In a Phase 0 trial, Kisqali (ribociclib) demonstrated good CNS penetration and inhibited Rb1 phosphorylation and tumor cell proliferation, resulted in a median progression-free survival of 9.7 weeks and a median overall survival of 7.8 months in patients (n=6) with recurrent glioblastoma with intact Rb1 expression and harboring deletion of CDKN2A or amplification of CDK4 or CDK6 (PMID: 31285369; NCT02933736).
|
31285369
|
|
CDKN2A loss
|
melanoma
|
sensitive
|
Trametinib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, a melanoma cell line with CDKN2A loss demonstrated sensitivity to Mekinist (trametinib) in culture, resulting in inhibition of cell growth (PMID: 27488531).
|
27488531
|
|
CDKN2A loss
|
melanoma
|
sensitive
|
Alvocidib
|
Preclinical |
Actionable |
In a preclinical study, melanoma cell lines with CDKN2A loss demonstrated a greater sensitivity to Alvocidib (flavopiridol) as compared to melanoma cell lines positive for CDKN2A (PMID: 12777976).
|
12777976
|
|
CDKN2A loss
|
Advanced Solid Tumor
|
no benefit
|
Ribociclib
|
Clinical Study |
Actionable |
In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with CDKN2A loss, CDK4, CDK6, CCND1, CCND2, or CCND3 amplification, or inactivating SMARCA4 mutations (PMID: 37424386; NCT02925234, ACTRN12616000931471).
|
37424386
|
|
CDKN2A loss
|
chordoma
|
sensitive
|
Abemaciclib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Abemaciclib (LY2835219) inhibited growth of chordoma cell lines with CDKN2A loss and loss of p16 protein expression in culture (PMID: 26183925).
|
26183925
|
|
CDKN2A loss
|
pancreatic cancer
|
no benefit
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial (TAPUR), patients with pancreatic cancer harboring a CDKN2A mutation or loss of CDKN2A (n=10) did not demonstrate an objective response or stable disease at 16 weeks when treated with single therapy, Ibrance (palbociclib), demonstrating a median progression-free survival of 7.2 weeks and an overall survival of 12.4 weeks (JCO Precision Oncology, Aug 14, 2019; NCT02693535).
|
detail...
|
|
CDKN2A loss
|
melanoma
|
resistant
|
Palbociclib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, a melanoma cell line deficient for CDKN2A demonstrated resistance to treatment with Ibrance (palbociclib) in culture (PMID: 27488531).
|
27488531
|
|
CDKN2A loss
|
chordoma
|
sensitive
|
Palbociclib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) inhibited expression of phosphorylated Rb and growth of chordoma cell lines with CDKN2A loss and loss of p16 protein expression in culture (PMID: 26183925).
|
26183925
|
|
CDKN2A loss
|
lung squamous cell carcinoma
|
predicted - sensitive
|
Palbociclib
|
Clinical Study - Cohort |
Actionable |
In a Phase II trial (NLMT), Ibrance (palbociclib) treatment resulted in an observed objective response rate (ORR) of 0% (0/19), durable clinical benefit rate (DCBR) of 22% (4/18), and medial progression-free survival (PFS) of 4.2 months in patients with lung squamous cell carcinoma harboring CDKN2A loss, with Bayesian estimated OR and DCBR of 3% and 24%, respectively, and Bayesian predictive probability of success for PFS >0.99 (PMID: 32669708, NCT02664935).
|
32669708
|
|
CDKN2A loss
|
lung non-small cell carcinoma
|
predicted - sensitive
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial (TAPUR), Ibrance (palbociclib) treatment resulted in a disease control rate of 31% with 1 partial response and 6 with stable disease at 16 weeks in patients with advanced or metastatic non-small cell lung cancer harboring CDKN2A loss or mutations (n=29), with a median progression-free survival of 8.1 weeks and a median overall survival of 21.6 weeks (PMID: 35050752; NCT02693535).
|
35050752
|
|
CDKN2A loss
|
lung non-small cell carcinoma
|
predicted - sensitive
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial, treatment with Ibrance (palbociclib) resulted in stable disease in 50% (8/16) of non-small cell lung cancer patients with CDKN2A loss (J Clin Oncol 32:5s, 2014 (suppl; abstr 8077)).
|
detail...
|
|
CDKN2A loss
|
lung adenocarcinoma
|
predicted - sensitive
|
Palbociclib
|
Clinical Study - Cohort |
Actionable |
In a Phase II trial (NLMT), Ibrance (palbociclib) treatment resulted in an observed objective response rate (ORR) of 4% (1/27), durable clinical benefit rate (DCBR) of 27.5% (8/29), and medial progression-free survival (PFS) of 3.3 months in patients with lung adenocarcinoma harboring CDKN2A loss, with Bayesian estimated OR and DCBR of 6% and 29%, respectively, and Bayesian posterior probability for PFS of 0.69 (PMID: 32669708, NCT02664935).
|
32669708
|
|
CDKN2A loss
|
renal cell carcinoma
|
sensitive
|
Palbociclib
|
Preclinical |
Actionable |
In a preclinical study, renal cell carcinoma cell lines with CDKN2A loss were sensitive to Palbociclib (PD-0332991) (PMID: 23898052).
|
23898052
|
|
CDKN2A loss
|
biliary tract cancer
|
no benefit
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial (TAPUR), patients with biliary cancer harboring a CDKN2A mutation or loss of CDKN2A (n=10) did not demonstrate an objective response or stable disease at 16 weeks when treated with single therapy, Ibrance (palbociclib), demonstrating a median progression-free survival of 7.3 weeks and an overall survival of 11.1 weeks (JCO Precision Oncology, Aug 14, 2019; NCT02693535).
|
detail...
|
|
CDKN2A loss
|
Advanced Solid Tumor
|
no benefit
|
Palbociclib
|
Clinical Study |
Actionable |
In a combined analysis of 2 clinical trials (DRUP, MoST), Ibrance (palbociclib) or Kisqali (ribociclib) monotherapy had limited efficacy and resulted in no objective responses, a 15% clinical benefit rate at 16 weeks, median progression-free survival of 4 mo, and median overall survival of 5 mo in previously treated advanced solid tumor patients (n=112) with CDKN2A loss, CDK4, CDK6, CCND1, CCND2, or CCND3 amplification, or inactivating SMARCA4 mutations (PMID: 37424386; NCT02925234, ACTRN12616000931471).
|
37424386
|
|
CDKN2A loss
|
pancreatic cancer
|
decreased response
|
Gemcitabine + Palbociclib
|
Preclinical |
Actionable |
In a preclinical study, Ibrance (palbociclib) antagonized the efficacy of Gemzar (gemcitabine) in pancreatic cancer cells with CDKN2A loss in culture (PMID: 25156567).
|
25156567
|
|
CDKN2A loss
|
pancreatic cancer
|
decreased response
|
GSK461364 + Palbociclib
|
Preclinical |
Actionable |
In a preclinical study, Ibrance (palbociclib) antagonized the efficacy of GSK461364 in pancreatic cancer cells with CDKN2A loss in culture (PMID: 25156567).
|
25156567
|
|
CDKN2A loss
|
pancreatic cancer
|
decreased response
|
HMN-214 + Palbociclib
|
Preclinical |
Actionable |
In a preclinical study, Ibrance (palbociclib) antagonized the activity of HMN-214 in pancreatic cancer cell lines with CDKN2A loss in culture (PMID: 25156567).
|
25156567
|
|
CDKN2A loss
|
brain glioblastoma multiforme
|
sensitive
|
Milciclib
|
Preclinical - Cell line xenograft |
Actionable |
In a preclinical study, Milciclib (PHA-848125AC) resulted in tumor regression in glioma cell line xenograft models with CDKN2A loss (PMID: 23347136).
|
23347136
|
|
CDKN2A loss
|
neuroendocrine tumor
|
sensitive
|
ZK 304709
|
Preclinical |
Actionable |
In a preclinical study, an orthotopic mouse model treated with ZK 304709 demonstrated an 80% tumor growth reduction in neuroendocrine tumor cells with CDKN2A loss (PMID: 18829975).
|
18829975
|
|
CDKN2A loss
|
Advanced Solid Tumor
|
predicted - sensitive
|
PF-00477736 + PF3644022
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of multiple cancer cell lines harboring CDKN2A loss and in Cdkn2a-depleted transformed cells in culture (PMID: 26140595).
|
26140595
|
|
CDKN2A loss
|
melanoma
|
sensitive
|
Abemaciclib + unspecified PD-1 antibody
|
Preclinical |
Actionable |
In a preclinical study, treatment with the combination of Verzenio (abemaciclib) and an anti-PD-1 antibody resulted in inhibition of both intracranial and extracranial tumor growth and improved survival compared to monotherapy or vehicle control in syngeneic mouse models of melanoma with loss of CDKN2A (PMID: 37611074).
|
37611074
|
|
CDKN2A loss NRAS mut
|
melanoma
|
predicted - sensitive
|
Abemaciclib
|
Case Reports/Case Series |
Actionable |
In a Phase I trial, Verzenio (abemaciclib) resulted in a partial response in a melanoma patient with CDKN2A loss and NRAS mutation (PMID: 27217383).
|
27217383
|
|
CDKN2A loss NRAS Q61K
|
melanoma
|
sensitive
|
Palbociclib + Trametinib
|
Preclinical - Cell line xenograft |
Actionable |
In a preclinical study, the combination of Ibrance (palbociclib) and Mekinist (trametinib) induced tumor regression in a mouse melanoma model expressing NRAS Q61K and harboring CDKN2A loss (PMID: 22983396).
|
22983396
|
|
CDKN2A loss NRAS Q61K
|
melanoma
|
sensitive
|
SBI-0640756
|
Preclinical |
Actionable |
In a preclinical study, SBI-0640756 delayed tumor growth of melanomas in mice with a genetic background of NRAS Q61K and CDKN2A loss (PMID: 26603897).
|
26603897
|
|
CDKN2A loss PIK3CA act mut
|
lung squamous cell carcinoma
|
predicted - sensitive
|
Buparlisib + Palbociclib
|
Preclinical - Pdx |
Actionable |
In a preclinical study, treatment with the combination of Buparlisib (BYL719) and Ibrance (palbociclib) resulted in increased tumor growth inhibition compared to either agent alone in patient-derived xenograft (PDX) models of lung squamous cell carcinoma harboring PIK3CA E542K or E545K mutations with p16 (CDKN2A) loss, including models that also had either PIK3CA amplification or PTEN loss (PMID: 30093452).
|
30093452
|
|
CDKN2A loss PIK3CA E542K PTEN loss
|
lung squamous cell carcinoma
|
sensitive
|
Buparlisib + Palbociclib
|
Preclinical - Pdx |
Actionable |
In a preclinical study, treatment with the combination of Buparlisib (BYL719) and Ibrance (palbociclib) resulted in increased tumor growth inhibition compared to either agent alone in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring PIK3CA E542K and PTEN loss, with p16 (CDKN2A) loss (PMID: 30093452).
|
30093452
|
|
CDKN2A loss PIK3CA E545K PIK3CA amp
|
lung squamous cell carcinoma
|
sensitive
|
Buparlisib + Palbociclib
|
Preclinical - Pdx |
Actionable |
In a preclinical study, treatment with the combination of Buparlisib (BYL719) and Ibrance (palbociclib) resulted in increased tumor growth inhibition compared to either agent alone in patient-derived xenograft (PDX) models of lung squamous cell carcinoma harboring PIK3CA E545K and PIK3CA amplification, with p16 (CDKN2A) loss (PMID: 30093452).
|
30093452
|
|
CDKN2A loss PIK3CA E542K PIK3CA amp
|
lung squamous cell carcinoma
|
sensitive
|
Buparlisib + Palbociclib
|
Preclinical - Pdx |
Actionable |
In a preclinical study, treatment with the combination of Buparlisib (BYL719) and Ibrance (palbociclib) resulted in increased tumor growth inhibition compared to either agent alone in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring PIK3CA E542K and PIK3CA amplification, with p16 (CDKN2A) loss (PMID: 30093452).
|
30093452
|
|
BRAF V600E/K CDKN2A loss RB1 pos
|
melanoma
|
predicted - sensitive
|
Palbociclib + Vemurafenib
|
Phase Ib/II |
Actionable |
In a phase I/II trial, Ibrance (palbociclib) plus Zelboraf (vemurafenib) was safe and resulted in an overall response rate (ORR) of 26.7% (4/15), disease control rate (DCR) of 80% (12/15), and progression-free survival (PFS) of 2.8 mo in metastatic melanoma patients with prior BRAF inhibitor treatment and BRAF V600E/K, CDKN2A loss, and RB1 expression, and an ORR of 27.8% (5/18), DCR of 83.3% (10/18) and 2.8 mo PFS when combined with pts without prior BRAF inhibitor treatment (PMID: 33947696; NCT02202200).
|
33947696
|
|
BRAF V600E CDKN2A loss CHEK2 dec exp RB1 pos
|
melanoma
|
predicted - resistant
|
Palbociclib + Vemurafenib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) and Zelboraf (vemurafenib) combination therapy in a melanoma cell line harboring BRAF V600E, CDKN2A loss, RB1 expression, and decreased expression of CHEK2 via siRNA resulted in increased cell proliferation and p-ERK levels compared to treated cells without decreased expression of CHEK2 in culture (PMID: 33947696).
|
33947696
|
|
BRAF V600E CDKN2A loss NRAS Q61K
|
melanoma
|
predicted - resistant
|
Cobimetinib + Vemurafenib
|
Case Reports/Case Series |
Actionable |
In a clinical case study, a melanoma patient harboring BRAF V600E and NRAS Q61K experienced progressive disease after a response to combination therapy with Zelboraf (vemurafenib) and Cotellic (cobimetinib), land was found to have acquired loss of CDKN2A (PMID: 34376578).
|
34376578
|
|
BRAF V600E CDKN2A loss NRAS G12V
|
melanoma
|
predicted - sensitive
|
Palbociclib + Trametinib
|
Preclinical - Pdx |
Actionable |
In a preclinical study, combination treatment with Ibrance (palbociclib) and Mekinist (trametinib) led to inhibition of tumor growth in a patient-derived xenograft (PDX) model of melanoma harboring BRAF V600E, NRAS G12V, and CDKN2A copy number loss (PMID: 34376578).
|
34376578
|
|
BRAF V600E CDKN2A loss NRAS G12V
|
melanoma
|
predicted - resistant
|
Cobimetinib + Vemurafenib
|
Case Reports/Case Series |
Actionable |
In a clinical case study, a melanoma patient harboring BRAF V600E experienced progressive disease after a response to combination therapy with Zelboraf (vemurafenib) and Cotellic (cobimetinib), likely due to acquisition of NRAS G12V and a loss of one copy of CDKN2A (PMID: 34376578).
|
34376578
|
|
BRAF V600E CDKN2A loss NRAS G12V
|
melanoma
|
predicted - sensitive
|
Palbociclib + Ulixertinib
|
Preclinical - Pdx |
Actionable |
In a preclinical study, combination treatment with Ibrance (palbociclib) and Ulixertinib (BVD-523) led to inhibition of tumor growth in a patient-derived xenograft (PDX) model of melanoma harboring BRAF V600E, NRAS G12V, and CDKN2A copy number loss (PMID: 34376578).
|
34376578
|
|
CDKN2A pos RB1 inact mut
|
glioblastoma
|
resistant
|
Palbociclib
|
Preclinical - Patient cell culture |
Actionable |
In a preclinical study, patient-derived glioblastoma cells harboring RB1 truncation mutation and expressing Cdkn2a were resistant to Ibrance (palbociclib) in culture (PMID: 22711607).
|
22711607
|
|
CDKN2A mutant
|
pancreatic cancer
|
no benefit
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial (TAPUR), patients with pancreatic cancer harboring a CDKN2A mutation or loss of CDKN2A (n=10) did not demonstrate an objective response or stable disease at 16 weeks when treated with single therapy, Ibrance (palbociclib), demonstrating a median progression-free survival of 7.2 weeks and an overall survival of 12.4 weeks (JCO Precision Oncology, Aug 14, 2019; NCT02693535).
|
detail...
|
|
CDKN2A mutant
|
biliary tract cancer
|
no benefit
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial (TAPUR), patients with biliary cancer harboring a CDKN2A mutation or loss of CDKN2A (n=10) did not demonstrate an objective response or stable disease at 16 weeks when treated with single therapy, Ibrance (palbociclib), demonstrating a median progression-free survival of 7.3 weeks and an overall survival of 11.1 weeks (JCO Precision Oncology, Aug 14, 2019; NCT02693535).
|
detail...
|
|
CDKN2A mutant
|
pancreatic cancer
|
not applicable
|
N/A
|
Guideline |
Risk Factor |
Germline mutations in CDKN2A results in familial malignant melanoma syndrome, which is associated with increased risk of developing pancreatic cancer (NCCN.org).
|
detail...
|
|
CDKN2A mutant
|
skin melanoma
|
not applicable
|
N/A
|
Guideline |
Risk Factor |
Germline CDKN2A mutations or polymorphisms are associated with increased risk of developing single or multiple primary cutaneous melanomas (NCCN.org).
|
detail...
|
|
CDKN2A mut PIK3CA mut
|
breast cancer
|
sensitive
|
Sapanisertib
|
Preclinical |
Actionable |
In a preclinical study, a breast cancer cell line harboring mutations in PIK3CA and CDKN2A demonstrated sensitivity to Sapanisertib (MLN0128) in culture (PMID: 25261369).
|
25261369
|
|
CDKN2A mut NRAS act mut
|
acute lymphoblastic leukemia
|
resistant
|
Trametinib
|
Preclinical |
Actionable |
In a preclinical study, human acute lymphoblastic leukemia cells harboring NRAS and CDKN2A mutations were insensitive to Mekinist (trametinib) in culture (PMID: 26343583).
|
26343583
|
|
CDKN2A inact mut
|
lung non-small cell carcinoma
|
predicted - sensitive
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial (TAPUR), Ibrance (palbociclib) treatment resulted in a disease control rate of 31% with 1 partial response and 6 with stable disease at 16 weeks in patients with advanced or metastatic non-small cell lung cancer harboring CDKN2A loss or mutations (n=29), with a median progression-free survival of 8.1 weeks and a median overall survival of 21.6 weeks (PMID: 35050752; NCT02693535).
|
35050752
|
|
CDKN2A inact mut
|
malignant spiradenoma
|
predicted - sensitive
|
Palbociclib
|
Case Reports/Case Series |
Actionable |
In a Phase II trial (TAPUR), Ibrance (palbociclib) treatment resulted in decreased size of the pulmonary nodules and right hilar mass, decreased pleural thickening and mediastinal lymphadenopathy, and an overall response in a patient with metastatic spiradenocarcinoma harboring a CDKN2A nonsense mutation (PMID: 38899982; NCT02693535).
|
38899982
|
|
CDKN2A inact mut
|
melanoma
|
decreased response
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, treatment with an immune checkpoint inhibitor resulted in a decreased response in melanoma patients with homozygous deletion of CDKN2A or loss of function CDKN2A mutations compared to patients with wild-type CDKN2A in one cohort, with a lower overall survival (OS) of 27.2 mo vs not yet reached and time to treatment failure of 10 vs 20.1 mo, respectively, but in a second cohort, there were no significant differences in OS (PMID: 34074656).
|
34074656
|
|
CDKN2A inact mut
|
lung non-small cell carcinoma
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in two cohorts of non-small cell lung cancer patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors (PMID: 34074656).
|
34074656
|
|
CDKN2A inact mut
|
bladder urothelial carcinoma
|
decreased response
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, treatment with an immune checkpoint inhibitor resulted in a decreased response in urothelial carcinoma patients with either homozygous deletion of CDKN2A or loss of function CDKN2A mutations compared to those patients with wild-type CDKN2A in two different cohorts, with an overall survival for each cohort of 8.8 and 11 mo. versus 25.2 and 19 mo, respectively, and time to treatment failure of 4.2 mo. versus 8.4 mo., respectively, in one cohort (PMID: 34074656).
|
34074656
|
|
CDKN2A inact mut
|
renal cell carcinoma
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in one cohort of renal cell carcinoma patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors, but in another cohort were significantly associated with reduced overall survival compared to wild-type CDNK2A (13 months vs 50 months, P=0.002)(PMID: 34074656).
|
34074656
|
|
CDKN2A inact mut
|
head and neck squamous cell carcinoma
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in two cohorts of head and neck squamous cell carcinoma patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors (PMID: 34074656).
|
34074656
|
|
CDKN2A inact mut
|
gastroesophageal cancer
|
not predictive
|
unspecified immune checkpoint inhibitor
|
Clinical Study - Cohort |
Actionable |
In a retrospective analysis, homozygous deletion of CDKN2A or loss of function CDKN2A mutations in one cohort of esophagogastric cancer patients were not predictive of overall survival or time to treatment failure when treated with immune checkpoint inhibitors, but in another cohort were significantly associated with reduced overall survival compared to wild-type CDKN2A (8 months vs 17 months, P=0.006) (PMID: 34074656).
|
34074656
|
|
CDKN2A R80*
|
stomach carcinoma
|
sensitive
|
Palbociclib
|
Preclinical - Cell line xenograft |
Actionable |
In a preclinical study, a gastric carcinoma cell line harboring CDKN2A R80* was sensitive to Ibrance (palbociclib) both in culture and in cell line xenograft models (PMID: 26380006, PMID: 20952405).
|
26380006
20952405
|
|
BRAF V600E CDKN2A R80*
|
skin melanoma
|
predicted - sensitive
|
Dabrafenib + Trametinib
|
Case Reports/Case Series |
Actionable |
In a clinical case study, a patient with metastatic giant sarcomatoid melanoma harboring BRAF V600E and CDKN2A R80* achieved a partial response following four months of treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib), and reached a complete response with regression of lung and bone metastases after one year of treatment (PMID: 32922664).
|
32922664
|
|
BRAF V600E CDKN2A R80*
|
rhabdomyosarcoma
|
predicted - sensitive
|
Dabrafenib + Palbociclib + Trametinib
|
Case Reports/Case Series |
Actionable |
In a clinical case study, the combination of Tafinlar (dabrafenib), Ibrance (palbociclib), and Mekinist (trametinib) resulted in a progression-free survival of 9 months in a patient with rhabdomyosarcoma harboring BRAF V600E and CDKN2A R80* (PMID: 33472910).
|
33472910
|
|
CDKN2A over exp SMARCB1 neg
|
rhabdoid cancer
|
decreased response
|
Palbociclib
|
Preclinical |
Actionable |
In a preclinical study, CDKN2A (p16) over expression was associated with decreased sensitivity to Ibrance (palbociclib) in a SMARCB1-negative malignant rhabdoid tumor cell line in culture (PMID: 21871868).
|
21871868
|
|
CDKN2A negative
|
lung non-small cell carcinoma
|
predicted - sensitive
|
Palbociclib
|
Phase II |
Actionable |
In a Phase II trial, Ibrance (palbociclib) treatment resulted in no objective response (0/16) and stable disease in 50% (8/16) of patients with advanced Cdkn2a-null (by IHC) non-small cell lung cancer, with a median overall survival (mOS) of 5.1 months for all patients and a mOS of 16.6 months in patients achieved stable disease (PMID: 30647837; NCT01291017).
|
30647837
|
|
CDKN2A negative
|
head and neck squamous cell carcinoma
|
predicted - sensitive
|
Cetuximab + Palbociclib
|
Case Reports/Case Series |
Actionable |
In a Phase I trial, Erbitux (cetuximab) and Ibrance (palbociclib) combination therapy was safe and resulted in a disease control rate of 89% (8/9, 2 partial responses, 6 stable disease) in patients with recurrent or metastatic head and neck squamous cell carcinoma, both responders had CDKN2A-negative tumors (PMID: 27311401).
|
27311401
|
|
CDKN2A negative
|
lung non-small cell carcinoma
|
sensitive
|
Everolimus + Palbociclib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) and Afinitor (everolimus) synergisticaly inhibited growth of Cdkn2a-null non-small cell lung cancer cell lines in culture (PMID: 30647837).
|
30647837
|
|
CDKN2A negative
|
lung non-small cell carcinoma
|
sensitive
|
Palbociclib + PF-04691502
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) and PF-04691502 synergisticaly inhibited growth of Cdkn2a-null non-small cell lung cancer cell lines in culture (PMID: 30647837).
|
30647837
|
|
CDKN2A negative
|
lung non-small cell carcinoma
|
sensitive
|
Palbociclib + Sirolimus
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) and Rapamune (sirolimus) synergisticaly inhibited growth of Cdkn2a-null non-small cell lung cancer cell lines in culture (PMID: 30647837).
|
30647837
|
|
CDKN2A hypermethylation
|
colorectal cancer
|
not applicable
|
N/A
|
Clinical Study - Meta-analysis |
Prognostic |
In a meta-analysis, CDKN2A promoter hypermethylation was associated with poor overall survival (HR=1.65, 95% CI 1.29-2.11), lymphovascular invasion (OR=1.68, 95% CI 1.15-2.47), and lymph node metastasis (OR=1.68, 95% CI 1.09-2.59) in colorectal cancer patients, and correlated significantly with poor overall survival in patients from Europe (HR=1.49, 95% CI 1.28-1.74) and Asia (HR=3.30, 95% CI 1.68-6.46) (PMID: 23703248).
|
23703248
|
|
CDKN2A H142R
|
B-cell acute lymphoblastic leukemia
|
sensitive
|
Palbociclib
|
Preclinical - Cell culture |
Actionable |
In a preclinical study, Ibrance (palbociclib) treatment inhibited viability of a B-cell acute lymphoblastic leukemia cell line expressing CDKN2A H142R in culture (PMID: 34369425).
|
34369425
|
|
CDKN2A A17fs
|
lung adenocarcinoma
|
predicted - sensitive
|
Palbociclib
|
Case Reports/Case Series |
Actionable |
In a Phase II trial (TAPUR), Ibrance (palbociclib) treatment resulted in a partial response in a patient with lung adenocarcinoma harboring CDKN2A A17fs (PMID: 35050752; NCT02693535).
|
35050752
|
