Genomic landscape of advanced basal cell carcinoma: Implications for precision treatment with targeted and immune therapies

Figures & data

Table 1. Patient profiles and treatment response.

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 alterations^2	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
2A^3	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^*
2B^3				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 ^*
3A^3	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
3B^3				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 A670S^4
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^*

¹ Patient's age is at the time of locally advanced/metastatic disease.

² Alterations in bold are considered potentially actionable by either an on- or off-label FDA approved drug.

³ Patients 2 and 3 each had multiple different biopsies sent for next generation sequencing. Patient 2 has been previously reported¹.

⁴ 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.

Figure 1. Genomic alterations identified* Top Panel: Total alterations (N = 62) identified by NGS on initial biopsy (N = 8 biopsies). Bottom Panel: Total alterations (N = 77) identified by NGS on initial and subsequent biopsies (N = 10 biopsies). *Some patients had multiple alterations in the same gene (i.e. TP53 and PTCH1).

Figure 2. Mean tumor mutational burden for cancers other than basal cell carcinoma (N = 1,637) vs. basal cell carcinoma (N = 9 biopsies with available data). P value calculated using Mann Whitney U test. Squares represent mean TMB. Bars represent the standard deviation of the mean. Abbreviations: BCC = basal cell carcinoma; mb = megabase; TMB = tumor mutational burden.