Sunscreens and cutaneous neoplasia:

Sunscreens and cutaneous neoplasia: Overview and update from the literature Catherine Olsen, Louise Wilson, Neela Biswas, Juhi Loyalka, David Whiteman Cancer Control Group QIMR Berghofer Medical Research Institute 2 Overview 1. Cutaneous neoplasia 2. Aims and objectives 3. Search strategies 4. Findings 5. Summary and conclusions QIMR Berghofer Medical Research Institute 3 QIMR Berghofer Medical Research Institute 4 1

Screening Cutaneous neoplasia Aims and objectives 1. Long-term neoplastic outcomes Melanoma BCC SCC Actinic keratoses Melanocytic nevi 2. Short-term neoplastic outcomes DNA mutations 1. Systematic search of literature relating sunscreen to cutaneous neoplasia outcomes 2. Abstract relevant data 3. Summarise where possible 4. Highlight gaps in knowledge 5. Conclusions QIMR Berghofer Medical Research Institute 5 QIMR Berghofer Medical Research Institute 6 Search strategy Literature SCC/BCC/melanoma Item Mesh terms Text terms Sunscreens sunscreening agents sunscreens sun protection factor Databases Keratinocyte cancers PubMed carcinoma, basal cell Web of carcinoma, Science squamous cell skin neoplasms Embase sunscreen sunblock spf Exclude sun lotion Case squamous reports cell carcinoma Editorial basal cell carcinoma BCC, SCC Comment non-melanoma skin cancer Letters keratinocyte cancer Actinic keratoses keratosis, actinic actinic keratos* Limit sunspot* to humans solar keratos* Nevi nevus nevi and melanomas nevus, pigmented nevus, intradermal dysplastic nevus syndrome Exclude nevi hospital-based naevi studies mole* QIMR Berghofer Medical Research Institute 7 Eligibility Identification Records identified Pub Med: 1819 Web of Sci: 104 EMBASE: 108 1803 records screened for LANGUAGE 1773 records screened for CONTENT 1056 records screened for SUNSCREEN 417 records screened for CUTANEOUS NEOPLASIA 191 records screened for INCLUSION CRITERIA 24 ELIGIBLE STUDIES Not human (n =16) Not in English (n =30) Reviews (n = 717) No exposure data (n = 639) No outcome data (n = 226), (n = 9) Other exclusion (n = 167) QIMR Berghofer Medical Research Institute 8 2

Screening Identification Eligibility Screening Literature SCC/BCC/melanoma Literature nevi Melanoma RCT (n =1) Cohort (n=1) Case-control (n=11) 24 ELIGIBLE STUDIES BCC/SCC RCT (n =1) Cohort (n=3) Case-control (n=1) Actinic keratosis RCT (n=4) Photo-aging RCT (n =2) QIMR Berghofer Medical Research Institute 9 Eligibility Identification Records identified Pub Med: 470 459 records screened for SUNSCREEN 17 records screened for CONTENT 15 records screened for SUNSCREEN 14 records screened for NEVI 11 records screened for ELIGIBLE STUDY DESIGN 4 ELIGIBLE STUDIES Not human (n =11) Not relevant (n =442) Reviews (n = 2) Not in English (n = 1) No outcome data (n = 3) Other exclusion (n = 7) QIMR Berghofer Medical Research Institute 10 Literature DNA mutations Literature DNA mutations Records identified Pub Med: 154 10 ELIGIBLE STUDIES 154 records screened for LANGUAGE 150 records screened for CONTENT 94 records screened for SUNSCREEN 43 records screened for DNA MUTATIONS 40 records screened for INCLUSION CRITERIA 10 ELIGIBLE STUDIES Not human (n = 0) Not in English (n =4) Reviews (n = 56) No exposure data (n = 51) No outcome data (n = 3) Other exclusion (n = 30) QIMR Berghofer Medical Research Institute 11 Natural UVR (n = 2) Observational UVB (n = 2) Experimental SSUVR (n = 6) Experimental QIMR Berghofer Medical Research Institute 12 3

Sunscreen and melanoma Sunscreen and melanoma ever use Cases/controls Exposure Location Study design (publication year) (Cohort size) assessment Green et al. 2011 Australia RCT 33/1621 Assigned Cho et al. 2005* USA Cohort 535/178,155 Self-report (F:152,949; M:25,206) Lazovich et al. 2011 USA Case-control 1167/1101 Self-report Youl et al. 2002* Australia Case-control 201/205 Self-report Westerdahl et al. 2000 Sweden Case-control 571/913 Self-report Whiteman et al. 1997* Australia Case-control 52/156 Self-report Autier et al. 1995* Germany, Case-control 418/438 Self-report Belgium, France Westerdahl et al. 1995 Sweden Case-control 400/640 Self-report Holly et al. 1995 USA Case-control 452/930 Self-report Herzfeld et al. 1993* USA Case-control 324/415 Self-report Beitner et al. 1990* Sweden Case-control 523/505 Self-report Osterlind et al. 1988 Denmark Case-control 474/926 Self-report Holman et al. 1986* Australia Case-control 507/507 Self-report QIMR Berghofer Medical Research Institute 13 QIMR Berghofer Medical Research Institute 14 Sunscreen and melanoma high vs low Sunscreen and melanoma regular use QIMR Berghofer Medical Research Institute 15 QIMR Berghofer Medical Research Institute 16 4

Sunscreen and melanoma high risk Sunscreen and melanoma low risk QIMR Berghofer Medical Research Institute 17 QIMR Berghofer Medical Research Institute 18 Sunscreen and keratinocyte cancers Sunscreen and keratinocyte cancers - SCC Cases/controls Location Study design (publication year) (Cohort size) van der Pols et al. 2006 Australia RCT 51 SCC 121 BCC Cohort 1621 Nicholas et al. 2009 USA Cohort 462 NMSC Cohort 2428 Grodstein et al. 1995 USA Cohort 197 SCC Cohort 107,900 Hunter et al. 1990 USA Cohort 771 BCC Cohort 73,366 Rosso et al. 1999 Switzerland Case-control 25SCC 120 BCC Exposure assessment RCT (assigned) Self-reported Self-reported Self-reported Self-reported QIMR Berghofer Medical Research Institute 19 QIMR Berghofer Medical Research Institute 20 5

Sunscreen and keratinocyte cancers - BCC Sunscreen and actinic keratoses Cases/controls Location Study design (publication year) (Cohort size) Carducci et al. 2015 Italy RCT 14 Sunscreen 14 Sunscreen +DNA repair enzymes Darlington et al. 2003 Australia RCT Sunscreen 557 No Sunscreen 559 Naylor et al. 1995 USA RCT Sunscreen 25 No Sunscreen 25 Thompson et al. 1993 Australia RCT Sunscreen 210 No Sunscreen 221 Exposure assessment RCT (assigned) RCT (assigned) RCT (assigned) RCT (assigned) QIMR Berghofer Medical Research Institute 21 QIMR Berghofer Medical Research Institute 22 Sunscreen and actinic keratoses Trial data - summary QIMR Berghofer Medical Research Institute 23 QIMR Berghofer Medical Research Institute 24 6

Sunscreen and nevi Sunscreen and nevi (publication year) Gallagher et al. (2000) Lee et al. (2005) Darlington et al. (2002) Luther et al. (1996) Location Study design Sample size Canada RCT 145 sunscreen 164 controls (6-7/9-10 yo) Australia Cohort 111 (12-13 yo) Germany Cohort 357 (4 yo) Followup Intervention/ exposure 3 years SPF30 (applied by parents when child in sun > 30 mins) Nevus assessment Clinical assessment 5 years Self-report sunscreen Counted 5 years Self-report sunscreen Clinical assessment (publication year) Gallagher et al. (2000) Lee et al. (2005) Darlington et al. (2002) Luther et al. (1996) Location Canada Findings Per protocol analysis number of new naevi (not ITT) Sunscreen 24 No sunscreen 28 (p=0.048) Australia Ratio of means Sunscreen use Always 1.0 (ref) Most of the time 1.82 (1.27-2.61) Sometimes/rare 1.08 (0.83-1.46) Germany Relative risk for increased number of nevi <24 vs >24 Sunscreen use Regular 1 Seldom 0.81 (0.65-1.01) Never 0.45 (0.23-0.75) QIMR Berghofer Medical Research Institute 25 QIMR Berghofer Medical Research Institute 26 UV damage in DNA If photolesions not repaired fixed mutation in daughter cells Cyclobutane pyrimidine dimers (CPD = TT, CT, TC) Pyrimidine (6-4) pyrimidone photoproducts (6-4TT) QIMR Berghofer Medical Research Institute 27 (year) Hacker 2013 Mahroos 2002 Liardet Ling 2000 Bykov 1998 Van Praag 1993 1991 Sample size Skin type Sunscreen regimen SPF 30+ 57 I-III 20 mins prior SPF 15 18 I-IV 30 mins prior SPF 15 8 I-III 15 mins prior SPF 15 sunscreen 4 II-III 15 mins prior SPF 4 (UVB vs UVA filters) 8 I-II 20 mins prior UVR type UVR Dose (MED) SS-UVR 2 Timing of biopsies post-uvr exposure 24 hrs 14 days SS-UVR 2 24 hrs SS-UVR 7.5 / 15 24 hrs 14 I-II SPF 10 UVB Up to 2 10 SPF 10 II III 30 mins prior 18 UVB sunscreen +/- 5- I-V MOP Sunscreen and DNA SS-UVR 2 2, 24, 48, 120 hrs SS-UVR 4 Immediately <15 min UVB 1 <2 min SS-UVR 2 wks sub-erythemal; 2 MED one week later <15 min QIMR Berghofer Medical Research Institute 28 7

Sunscreen and DNA Sunscreen and DNA (year) Hacker 2013 Mahroos 2002 Liardet Ling 2000 Bykov 1998 Van Praag 1993 1991 DNA markers CPD, p53, Ki67, cell counts CPD, p53, 8OHDG P53 (6-4)PP Unsecheduled DNA synthesis QIMR Berghofer Medical Research Institute 29 (year) Hacker 2013 Mahroos 2002 Liardet Ling 2000 Bykov 1998 Van Praag 1993 1991 DNA markers CPD, p53, Ki67, cell counts CPD, p53, 8OHDG P53 (6-4)PP Unsecheduled DNA synthesis Outcome Complete abrogation of all effects. No thymine dimers in skin with sunscreen applied per protocol. Partial protection from partial application. SPF 15 sunscreen + 7.5 MED SS-UVR = 0.5 MED unprotected SPF 15 sunscreen + 15 MED SS-UVR = 1 MED unprotected s 2-3-fold decrease P53 expression 4.4-fold reduction SPF 4 sunscreen + 4 MED SS-UVR = 1 MED unprotected DNA damage after SPF 10 sunscreen = 0.05-0.10 unprotected no specific fluorescence. Indicating no DNA damage Highly significant reduction in UDS for sunscreen treated skin (p<0.001) QIMR Berghofer Medical Research Institute 30 Sunscreen for melanoma control? Sunscreen for melanoma control? Queensland Institute of Medical Research 31 8

Sunscreen for melanoma control? Sunscreen for melanoma control? ~100% ~0% QIMR Berghofer Medical Research Institute 33 Challenges with current knowledge The Prevented Fraction 1.0 1. Very few trials 2. Residual confounding in observational studies 3. Heterogeneity of measures Cases of cancer Rate ratio 0.5 Green et al, J Clin Oncol. 2011; 29:257-263 Sunscreen type; frequency; duration; dose etc Outcomes 4. Evolving understanding of UVA, UVB and carcinogenesis 0.0 no sunscreen sunscreen QIMR Berghofer Medical Research Institute 35 Queensland Institute of Medical Research 36 9

The Prevented Fraction 1.0 Rate ratio Green et al, J Clin Oncol. 2011; 29:257-263 Agent Sunscreen Regular use SPF15+ when outdoors Prevalence Men 21% Women 35% The Prevented Fraction Site of cancers prevented Effect size Melanoma 0.50 (0.24-1.02) SCC Skin 0.65 (0.45-0.94) Cases of cancer 0.5 0.0 Source: Olsen et al. Aust NZ J Public Health 2015; 39:471-6 no sunscreen sunscreen Queensland Institute of Medical Research 37 QIMR Berghofer Medical Research Institute 38 The Prevented Fraction The Potential Impact Fraction Agent Sunscreen Regular use SPF15+ when outdoors Prevalence Men 21% Women 35% Site of cancers prevented Effect size Number prevented (PF) Melanoma 0.50 (0.24-1.02) 1,729 (14%) SCC Skin 0.65 (0.45-0.94) 14,192 (9.3%) Source: Olsen et al. Aust NZ J Public Health 2015; 39:471-6 QIMR Berghofer Medical Research Institute 39 QIMR Berghofer Medical Research Institute 40 10

The Potential Impact Fraction The Potential Impact Fraction QIMR Berghofer Medical Research Institute 41 QIMR Berghofer Medical Research Institute 42 The Potential Impact Fraction QIMR Berghofer Medical Research Institute 43 QIMR Berghofer Medical Research Institute 44 11