Table 1.
Patient | Age (years)1 | Sex | Locally advanced or metastatic disease | TMB (mutations/mb) | Number of characterized alterations | Potentially actionable alterations with either an on or off-label FDA approved drug | Genomic alterations2 | Best response/PFS (months) to a PD-1 inhibitor (agent) | Best Response/PFS (months) to a Hedgehog inhibitor (agent) | Disease status at biopsy |
---|---|---|---|---|---|---|---|---|---|---|
1 | 65 | M | Locally advanced (large lesion of right auricle with recurrent disease after multiple resections and radiation) | 96 | 8 | 6 | PTCH1 Q576* | PR/34.2+ (vismodegib) | Locally advanced disease | |
ERBB4 D861N | ||||||||||
CDKN2A p14ARF P105S | ||||||||||
EPHA3 E930K | ||||||||||
KEAP1 R169C | ||||||||||
TP53 G266R | ||||||||||
TP53 R196* | ||||||||||
TP53 S33fs*10 | ||||||||||
2A3 | 56 | M | Metastatic | N/A | 10 | 5 | PTCH1 Q1366* | PR/17.6+ (nivoulmab) | PD/2.0 (vismodegib/paclitaxel) | Metastatic disease |
PTCH1 W197* | Also received sonidegib/buparlisib with progression at 1.9 months | |||||||||
CDKN2A P81L | ||||||||||
TP53 P278S | ||||||||||
CDKN1A R140Q | ||||||||||
CTNNA1 R383H | ||||||||||
LRP1B splice site 9121-1G>A | ||||||||||
NOTCH1 W287* | ||||||||||
SLIT2 K325* | ||||||||||
SMARCA4 Q1166* | ||||||||||
2B3 | 103 | 19 | 11 | CD274 (PD-L1) amplification | Metastatic disease | |||||
FLT1 E487K | ||||||||||
JAK2 amplification | ||||||||||
PDCD1LG2 (PD-L2) amplification | ||||||||||
PDGFRA E459K | ||||||||||
PIK3R2 Q412* | ||||||||||
PTCH1 Q1366* | ||||||||||
PTCH1 W197* | ||||||||||
CDKN2A P81L | ||||||||||
TP53 P278S | ||||||||||
CDKN1A R140Q | ||||||||||
CTNNA1 R383H | ||||||||||
LRP1B splice site 9121-1G>A | ||||||||||
LRP1B W2334* | ||||||||||
MLL2 splice site 4132-1G>A | ||||||||||
NOTCH1 W287* | ||||||||||
SLIT2 K325* | ||||||||||
SMARCA4 Q1166* | ||||||||||
TERT promoter -139_-138CC>TT * | ||||||||||
3A3 | 53 | F | Metastatic | 90 | 6 | 2 | PTCH1 E684* | PR/3.8 (nivolumab) | PR/4.5 (vismodegib) | Locally advanced disease |
TP53 R342* | ||||||||||
LRP1B 2553* | ||||||||||
WT1 S461F | ||||||||||
KDM5A P325S | ||||||||||
CREBBP H397fs*38 | ||||||||||
3B3 | 90 | 12 | 5 | PTCH1 E684* | Metastatic disease | |||||
CD274 (PD-L1) amplification | ||||||||||
JAK2 amplification – equivocal | ||||||||||
PDCD1LG2 (PD-L2) amplification | ||||||||||
TP53 R342* | ||||||||||
CREBBP H397fs*38 | ||||||||||
KDM5A P325S | ||||||||||
LRP1B R2553* | ||||||||||
STAG2 Q914* | ||||||||||
TAF1 splice site 2119-1G>A | ||||||||||
TERT promoter -138_-139CC>TT | ||||||||||
WT1 S461F | ||||||||||
4 | 66 | M | Locally advanced (involving left auricle and left lower extremity) | 52 | 6 | 3 | PTCH1 Q889* | Locally advanced | ||
GRM3 E49K | ||||||||||
TP53 G245N | ||||||||||
TP53 H179Y | ||||||||||
NOTCH1 Q475* | ||||||||||
NOTCH2 Q1870* | ||||||||||
5 | 62 | M | Locally advanced (unresectable 10 × 11 cm tumor located on back) | 53 | 12 | 6 | PTCH1 R770*-subclonal | CR/8.1+* (Nivolumab and vismodegib) | CR/8.1+* (Nivolumab and vismodegib) | Locally advanced disease |
PTCH1 spice cite 1504-1G>T | ||||||||||
PTEN splice cite 210–2A>T | ||||||||||
ASXL1 Q760* | ||||||||||
INPP4B W521* | ||||||||||
KEL 130Q | ||||||||||
PIK3R1 R534* | ||||||||||
RAC1 P29S | ||||||||||
TERT promoter-124C>T | ||||||||||
TP53 Q100* | ||||||||||
TP53 R196* | ||||||||||
WT1 C350R | ||||||||||
6 | 69 | M | Locally advanced (lesion involving the right neck/submental area with recurrent disease following multiple surgeries and radiation) | 3 | 2 | 0 | TET2 F1287fs*76 | PR/12.2 (vismodegib) | Locally advanced | |
GLI1 A670S4 | ||||||||||
7 | 61 | M | Locally advanced (large nodular lesion involving the nose with patient refusing surgery and radiation) | 20 | 8 | 3 | SMO W535L | PR/9.2 (vismodegib) | Locally advanced | |
KDR G1145E | ||||||||||
ARID1A Q1894* | ||||||||||
MLL2 S3463fs*39 | ||||||||||
PIK3R1 R534* | ||||||||||
RUNX1 S100F | ||||||||||
SPTA E638K | ||||||||||
TERT promoter-146C>T | ||||||||||
8 | 50 | F | Metastatic | 102 | 10 | 5 | PTCH1 G854* | PD/2.5 (pembrolizumab) | PR/11.1 (vismodegib) | Metastatic |
PTCH1 splice cite 2560+1G>A | ||||||||||
TSC1 loss exon 9–23 | ||||||||||
GRIN2A S929F | ||||||||||
MAGI2 W688* | ||||||||||
NOTCH2 R1838* | ||||||||||
RBM10 splice cite 633+1G>A | ||||||||||
TERT promoter-146C>T | ||||||||||
TP53 Q136* | ||||||||||
TP53 R213* |
Patient's age is at the time of locally advanced/metastatic disease.
Alterations in bold are considered potentially actionable by either an on- or off-label FDA approved drug.
Patients 2 and 3 each had multiple different biopsies sent for next generation sequencing. Patient 2 has been previously reported1.
The variant GLI1 p.A670S is common in healthy people from European origin (1/333 individuals – 1000 Genomes database) and is considered neutral by several algorithms (SIFT, Provean, Polyphen-2). However, these algorithms only consider the similarities between amino acids (A and S are both polar uncharged amino acids). The addition of a serine residue within Gli1 sequence creates an additional phosphorylation site, and Gli1 is exclusively regulated by phosphorylation.
The new phosphorylation site created by the A670S variant is not depending on PKA, and therefore may lead to the activation of the Hedgehog pathway. This variant might be pathogenic in the context of basal cell carcinoma.
Patient 5 received the combination of nivolumab and vismodegib.
All three patients who received immunotherapy as monotherapy received immunotherapy after treatment with a hedgehog inhibitor.