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In this issue, Singh et al. (2015) also report the effects of 17AAG on the biomarkers of chronic UVR-induced photoaging of the skin. Overexpression of matrix metalloproteinases (MMPs) in UV-exposed skin has been implicated in the wrinkling of the skin or premature aging of the skin that is known as photoaging of the skin. Topical treatment of the SKH-1 hairless mouse skin with 17AAG before and after UVR exposure resulted in decreased levels of MMP-2 and MMP-9 proteins as compared with the mouse skin, which was not treated with 17AAG but exposed to UVR. These results suggest that 17AAG treatment may protect the skin from photoaging through inhibition of MMPs. Singh et al. (this issue, 2015) have demonstrated convincingly that 17AAG has the ability to inhibit UVR-induced SCC development and also inhibits selected biomarkers of photoaging of the skin. However, UVR-induced development of SCCs accompanies expression and activation of several oncogenic signal transduction pathways, as summarized in Figure 1. Thus, more rigorous, mechanism-based studies are warranted to establish the molecular mechanisms underlying prevention of UVR-induced SCCs in the skin by 17AAG. Further studies may reveal a broader mechanism of action of Hsp90 inhibitor, 17AAG. CONFLICT OF INTEREST

The author states no conflict of interest.

ACKNOWLEDGMENTS This work is partially supported by the National Institutes of Health/NCI (CA140832, CA140197) and Veterans Administration Merit Review Award (1I01BX001410).

REFERENCES Aziz MH, Manoharan HT, Verma AK (2007) Protein kinase C epsilon, which sensitizes skin to sun’s UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res 67:1385–94 Baliga MS, Katiyar SK (2006) Chemoprevention of photocarcinogenesis by selected dietary botanicals. Photochem Photobiol Sci 5:243–53 Cullinan SB, Whitesell L (2006) Heat shock protein 90: a unique chemotherapeutic target. Semin Oncol 33:457–65 Goetz MP, Toft D, Reid J et al. (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin

in patients with advanced cancer. J Clin Oncol 23:1078–87 Gould CM, Kannan N, Taylor SS et al. (2009) The chaperones Hsp90 and Cdc37 mediate the maturation and stabilization of protein kinase C through a conserved PXXP motif in the C-terminal tail. J Biol Chem 284:4921–35 Heath EI, Hillman DW, Vaishampayan U et al. (2008) A phase II trial of 17-allylamino-17demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin Cancer Res 14:7940–6 Miyata Y, Nakamoto H, Neckers L et al. (2013) The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des 19:347–65 Nichols JA, Katiyar SK (2010) Skin photoprotection by natural polyphenols: anti-inflammatory, anti-oxidant and DNA repair mechanisms. Arch Dermatol Res 302:71–83

Pacey S, Gore M, Chao D et al. (2012) A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs 30:341–9 Singh A, Singh A, Sand JM et al. (2015) Topically applied Hsp90 inhibitor 17AAG inhibits ultraviolet radiation-induced cutaneous squamous cell carcinomas. J Invest Dermatol 135:1098–107 Soti C, Nagy E, Giricz Z et al. (2005) Heat shock proteins as emerging therapeutic targets. Br J Pharmacol 146:769–80 Wheeler DL, Martin KE, Ness KJ et al. (2004) Protein kinase C epsilon is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas. Cancer Res 64:7756–65

See related letter to the editor on pg 1190

Focus on Early Detection to Reduce Melanoma Deaths Alan C. Geller1, Susan M. Swetter2 and Martin A. Weinstock3 Thin fatal melanomas are a relatively new clinical and public health concern, representing an estimated 20% of melanoma deaths. Understanding this phenomenon will require a multi-pronged approach, including in-depth investigation of its behavioral and biological underpinnings. As we proceed with relevant studies, the benefits in lives saved will grow via early detection. Journal of Investigative Dermatology (2015) 135, 947–949; doi:10.1038/jid.2014.534

Whiteman and colleagues (this issue, 2014) contribute to our understanding and management of melanoma from the public health perspective by reinforcing the importance of measures that reduce the number of deaths from both thin and thick melanomas (Whiteman et al., 2014). We wish to underscore three key points: (a) the comprehensive nature of our quest to reduce deaths from melanoma, (b) the need to understand the nature of thin melanomas that are ultimately fatal, and (c) the

focus on early detection as the highest priority in the effort to reduce melanoma deaths. Mortality rates in the USA and elsewhere are declining for four of the five cancers most amenable to early detection. Cancers of the breast, cervix, colon, and prostate have demonstrated mortality reductions, ranging from 20 to 60% over the past 25 years (www.cdc.gov/nchs). However, if current trends in cancer death rates continue, melanoma will be the only cancer

1

Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, Massachusetts, USA; 2Department of Dermatology, Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA and 3Center for Dermatoepidemiology, VA Medical Center, Providence Department of Dermatology, Rhode Island Hospital Departments of Dermatology and Epidemiology, Brown University, Providence, Rhode Island, USA Correspondence: Alan C. Geller, Department of Social and Behavioral Sciences, Harvard School of Public Health, Kresge 718, 677 Huntington Avenue, Boston, Massachusetts 02215, USA. E-mail: [email protected]

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COMMENTARY

Clinical Implications 

Successful screening programs have led to as many ultimately fatal melanomas being diagnosed while still ‘‘thin’’ (o1.0 mm in greatest thickness), such that in absolute numbers more patients now die of thin compared with thick (44.0 mm) melanomas.



Multi-level investigations will be required to identify thin but ultimately fatal melanomas.



Focus on early detection remains the most important priority.

included in Healthy People 2020 that will not meet the targets for reductions in cancer deaths (US Department of Health and Human Services, 2014). After decade-long increases in both melanoma incidence and mortality rates, we are only now seeing the first signs of a plateau in mortality––due primarily to early detection of melanomas that have not yet metastasized. An increasing proportion of melanoma deaths resulted from thin lesions in the 1990–2009 Queensland Cancer Registry (QCR) analysis (Whiteman et al., 2014). The 296 ultimately fatal cases that arose from thin melanomas represent an estimated 3% of all melanomas diagnosed at p1 mm (T1) during the most recent 5 years. This is very similar to the 2.7% mortality in T1 melanoma from US SEER data (Criscione and Weinstock, 2010). Notwithstanding recent major advances in immunotherapies and molecularly targeted therapies for patients with advanced melanoma, early detection and secondary prevention strategies remain the most effective means of preventing death from melanoma, both in the short-term and in the foreseeable future. For the millions of high-risk unscreened individuals, mortality reductions from the population-based screening campaign in Schleswig-Holstein, Germany (Katalinic et al., 2012), and the workplace education and screening intervention at Lawrence Livermore National Laboratory, (Schneider et al., 2008), as well as other epidemiologic investigations, indicate large potential benefit in this approach. In 2009, the United States Preventive Services Task Force (USPSTF) recommended neither for nor against routine skin cancer screening of the general public by 948

primary care physicians, on the basis of evidence published through 2007, assigning an ‘‘insufficient’’ rating (USPSTF, 2009). Since the USPSTF review, however, evidence of reduced melanoma mortality rates associated with clinical skin screening has increased substantially, and the USPSTF is now reviewing most recent evidence (personal communication). To reduce the mortality rate for melanoma in the USA and in other nations, it will be important to employ a comprehensive approach that encompasses an understanding of the biology of this tumor, building the requisite social structures needed to detect early cancers (trained screeners, referral networks, reimbursement), and keen awareness of the epidemiologic trends associated with fatal melanoma. A better understanding of the interplay between melanoma biology and human behavior is needed. Contemporary concepts in the taxonomy of melanoma identify distinct molecular, genetic, anatomic, and environmental factors that affect melanoma risk and lethality. However, the growth kinetics of certain histological subtypes of melanoma also appear to have a role in prognosis. (1) Nodular melanoma (NM) comprises fewer than 15% of all melanomas but represents a disproportionate number of fatal cases, and it remains a tumor that often eludes early detection on the basis of clinical characteristics alone. (2) The sex disparity in melanoma mortality continues to grow. In the USA, the mortality rates for white women are virtually unchanged for 35 years (1.94/ 100,000 in 1976 to 1.93/100,000 in 2011), whereas rates for men have risen nearly 50% (3.10/100,000 to 4.61/ 100,000) during the same period

Journal of Investigative Dermatology (2015), Volume 135

(www.cdc.gov/nchs). High-mitotic rate and ulceration, both bad prognostic features in melanoma, are far more prevalent in the lesions of elderly men than in any other demographic group (Shen et al., 2014), and, even younger men (p40 years) demonstrate worse survival compared with women, when matched for tumor thickness, histologic subtype, anatomic location, and the presence/extent of metastasis. Now a relatively new conundrum emerges, one that would have been unimaginable a generation ago. Major advances in awareness and recognition of disease by public and professionals alike have led to an estimated 70% of all invasive melanomas in the USA, Australia, and Western Europe being detected at p1 mm, and incidence rates are rising most sharply for these thin melanomas. First noted in the US population–based SEER registry (Criscione and Weinstock, 2010) and now in Queensland (Australia) by Whiteman and colleagues, we see a significant minority of deaths in individuals diagnosed with melanoma p1 mm. Merging incidence and death files from the QCR, the authors found that 19% of all melanoma deaths for the period 1990–2009 arose from individuals diagnosed with melanoma p1 mm; this rate rose from 14% of all deaths in 1990–1994 to 23% in 2005– 2009. Most strikingly, in Queensland, melanomas p1 mm at the time of diagnosis cause more deaths (n ¼ 296) compared with melanomas in any other thickness category (Whiteman et al., 2014). Thus, even though early detection of tumors reduces mortality, detection at p1 mm thickness does not necessarily mean cure. A more granular description of factors associated with fatal thin melanomas is beyond the scope of this Commentary. Drawing on large population-based and case-control studies, the usual factors generally associated with later-stage, poor outcome tumors emerge even with thin melanomas, including patient demographics (older men), tumor biology (NM and acral lentiginous subtypes, ulceration, high-mitotic rate), and anatomic site (head, neck, and trunk; Murali et al., 2012). Patients with melanoma p1 mm with no ulceration and

COMMENTARY

low mitotic rate (T1a) demonstrate 5-year survival rates of 497%, and this increases to 499% for T1a tumors p0.5 mm. However, subsets of melanomas 40.75 mm with ulceration and/or mitotic rate Z1 mm2 (a far more common finding than ulceration in T1 melanoma) have shown higher rates of sentinel lymph node positivity and worse survival. This raises the question whether more of the deaths in the QCR occurred in individuals closer to 1 mm and/or in those who had histologic features that increased their inherent potential for metastasis. We are faced with a pressing clinical quandary of how to differentiate the thin, ostensibly curable melanomas from those that will recur with metastasis. As we improve the identification of early melanomas, we will run the risk of increasing overdiagnosis, with resulting increases in skin surgeries, referrals, anxiety, and costs. We agree with Whiteman et al. (2014), regarding the need for more insight into the clinical and molecular features of thin melanomas. Gimotty and Guerry (2010) have called for new prognostic biomarkers of metastases for patients with thin melanoma arguing further that solely relying on histopathological attributes and one’s sentinel lymph node status are not adequately informative. Molecular techniques may also help identify thin melanomas that will have more aggressive behavior. Arguably, patients who have ‘‘positive’’ biomarkers should be considered candidates for sentinel lymph node biopsy staging and closer follow-up. Whiteman et al conclude their article with a call for a ‘‘very high priority’’ on the importance of primary prevention. Although primary prevention initiatives

in Australia have been successful, we have two concerns: 



The time lag between exposure to ultraviolet radiation, the target of all major primary prevention efforts, and the diagnosis of melanoma is generally 15 or more years and often several decades; death from ultimately fatal thin melanoma occurred an additional 7 years after diagnosis in Queensland. Therefore, even if we could reduce exposure substantially tomorrow, it would take decades to realize an impact on mortality. Public health efforts for over 40 years have aimed at reducing ultraviolet radiation exposure, particularly in childhood and early adulthood; yet, for the overall worldwide population the net impact has been modest at best. This frustrating reality was illustrated in the United States by the Youth Risk Behavior Survey that recently found that among high school seniors, only 6% of boys and 16% of girls used sunscreen with sun protection factor 15 or higher most or all of the time, whereas 9% of boys and 32% of girls used indoor tanning devices (Eaton et al., 2012).

We do not suggest that primary prevention be abandoned, but rather that early detection is the best approach for substantial melanoma mortality reduction as indicated by the studies in Schleswig-Holstein and at the Lawrence Livermore National Laboratories (Schneider et al., 2008; Katalinic et al., 2012), as well as by several case-control studies. The evidence for melanoma mortality reduction by early detection has strengthened considerably in the last decade, and the benefit in lives saved

may be observed in the next decade if screening is implemented widely. REFERENCES Criscione VD, Weinstock MA (2010) Melanoma thickness trends in the United States, 19882006. J Invest Dermatol 130:793–7 Eaton DK, Kann L, Kinchen S et al. (2012) Youth risk behavior surveillance–United States, 2011. MMWR Morb Mortal Wkly Rep 61:41 Gimotty PA, Guerry D (2010) Prognostication in thin cutaneous melanomas. Arch Pathol Lab Med 134:1758–63 Katalinic A, Waldmann A, Weinstock MA et al. (2012) Does skin cancer screening save lives?: an observational study comparing trends in melanoma mortality in regions with and without screening. Cancer 118: 5395–402 Murali R, Scolyer RA, Thompson JF (2012) Can we better identify thin cutaneous melanomas that are likely to metastasize and cause death? Ann Surg Oncol 19:3310–2 Schneider JS, Moore DH, Mendelsohn ML (2008) Screening program reduced melanoma mortality at the Lawrence Livermore National Laboratory, 1984 to 1996. J Am Acad Dermatol 58:741–9 Shen S, Wolfe R, McLean CA et al. (2014) Characteristics and associations of highmitotic rate melanoma. JAMA Dermatology E1–8 Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality - All COD, Aggregated With State, Total U.S. (1969-2010) oKatrina/ Rita Population Adjustment4, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013. Underlying mortality data provided by NCHS (www.cdc.gov/nchs) U.S. Department of Health and Human Services (2014) The Surgeon General’s Call to Action to Prevent Skin Cancer. Washington, DC: U.S. Department of Health and Human Services, Office of the Surgeon General USPSTF (2009) Screening for skin cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 150:188–93 Whiteman D, Baade P, Olsen C (2014) More people die from thin melanoma ( ¼ o1 mm) than thick melanomas (44 mm) in Queensland, Australia. J Invest Dermatol 135:1190–3

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Focus on early detection to reduce melanoma deaths.

Thin fatal melanomas are a relatively new clinical and public health concern, representing an estimated 20% of melanoma deaths. Understanding this phe...
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