Highlights in Melanoma Research and Treatment
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Dana-Farber dermatologist Jennifer Lin, MD, discusses the latest research and treatment for melanoma. This presentation was originally given as part of Dana-Farber's Tuesday Talks speaker series. In this talk, Lin provides an overview of melanoma, including recent research, progress and future goals.
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Highlights in Melanoma Research and Treatment
- 1. Approaching Melanoma in 2012: Highlights of the Progress and the Work Ahead Jennifer Y Lin, MD Melanoma Program, Dana-Farber/Brigham & Women’s Cancer Center Department of Dermatology, Brigham & Women’s Hospital
- 2. Disclosure of Relevant Relationships with Industry I do not have any relevant Relationships with industry.
- 3. Melanoma Program at DFCI/BWH Cancer Center Pigmented Lesion Clinic at BWH and Multidisciplinary Melanoma Clinic at DFCI Collaboration with pathologists, medical oncologists, surgical oncologists, radiation oncologists Weekly tumor board to discuss cases Monthly lectures to discuss the latest advances in the clinical and research aspects of melanoma
- 4. Goals 1. What are my risks of developing melanoma? 2. How can I decrease my risk? 3. What are my options if I have been diagnosed with melanoma? 4. What is in the horizon for melanoma?
- 5. Erdmann F et al. Int J Cancer. 2012.
- 8. 5th most common 7th most common • 76,250 new cases every year • 9,180 men and women will die from melanoma www.cancer.gov.
- 9. Increasing incidence of melanoma among young adults (ages 18-39) 1970- 2009 4x 8x
- 10. Death from melanoma in older men is disproportionately high J Amer Acad Dermatol. 2007 vol. 57 (4) pp. 555-72.
- 11. Detection of thin melanomas has improved JID. (2010) 130, 793–797
- 13. Genetic Environmental •skin color •ultraviolet radiation •family history of • sunburns melanoma • # of moles •prior history of •immunosuppression melanoma •lack of access •atypical nevi •lack of education
- 14. Genetic Environmental •skin color •ultraviolet radiation •family history of • sunburns melanoma • # of moles •prior history of •immunosuppression melanoma •lack of access •atypical nevi •lack of education
- 15. Genetic Environmental •skin color •ultraviolet radiation •family history of • sunburns melanoma • # of moles •prior history of •immunosuppression melanoma •lack of access •atypical nevi •lack of education
- 16. Fitzpatrick’s Skin Phototype Facultative pigmentation Constituitive pigmentation tan burn 1 2 3 4 5 6 library.thinkquest. org
- 17. Skin Phototype Loss of function MC1R polymorphisms red hair fair skin light eyes freckling 1 2 3 4 5 6 library.thinkquest. org
- 18. Genetic Environmental •skin color •ultraviolet radiation •family history of • sunburns melanoma • # of moles •prior history of •immunosuppression melanoma •lack of access •atypical nevi •lack of education
- 19. Genetic • full body skin •skin color exams •family history of melanoma • monthly self •prior history of checks melanoma •atypical nevi
- 21. Benign acquired nevi • small, round, symmetric • can also be pink! and raised • acquired from childhood through adulthood • related to sun exposure Miller A and Mihm, M. NEJM, 2006.
- 23. Atypical nevi • diagnosis based on clinical and pathologic features • some evidence to suggest it could be a precursor lesion, but we lack diagnostic tools • Dysplastic Nevus Syndrome - Familial atypical multiple mole melanoma (FAMMM) Syndrome, B-K mole syndrome Miller A and Mihm, M. NEJM, 2006.
- 24. Atypical nevus (AN) and risk for melanoma • 1 AN 2.3x • <3-5 AN 4x • >5-10 AN 10x
- 25. ABCD’s A B C D Asymmetry Border Colors Diameter > Irregularity ¼ inch http://visualsonline.cancer.gov/about.cfm
- 26. E is for Evolution • Lesions that are changing – multiple colors – increasing in size – itching or pain – unlike any of your other moles
- 27. Genetic Environmental •skin color •ultraviolet radiation •family history of • sunburns melanoma • # of moles •prior history of •immunosuppression melanoma •lack of access •atypical nevi •lack of education
- 28. Environmental Genetic •ultraviolet •skin color radiation •family history of • sunburns melanoma • # of moles •prior history of •immunosuppression melanoma •lack of access •atypical nevi •lack of education
- 31. UVR is a small component of solar radiation at the Earth’s surface SOLAR RADIATION = Visible light + Infrared + Ultraviolet light 10% (UVA, UVB) 40% 50% UVC UVB (5%) UVA (95%)
- 32. UVR – depth of penetration Depth of penetration increases with wavelength until about 1100 nm
- 33. Tanning is addictive… J Am Acad Derm. 51(1): 45-51, 2004.
- 34. Tanning booths • 12X more UVA than sun, small amounts of UVB • Earlier exposure (high school vs. post college) associated with increased risk of skin cancer
- 35. Does sunscreen work? Does it decrease risk of skin cancer?
- 36. • 1,621 patients applied sunscreen daily for years • 14 year follow-up • 50% decrease in all melanoma, 73% decrease in invasive melanoma J Clin Onc. 29 (3): 257-263, 2011.
- 37. Sun Protection Factor (SPF) • SPF 15 = 15 times the UVB dose required to achieve MED • Practically this translates to amount of time: • If a patient’s skin normally takes 10 minutes to burn, the use of an SPF 15 sunscreen will now take him/her 150 minutes to burn. • Primarily a measure of UVB protection
- 38. Sunscreen (chemical) Active Ingredients weak, stable Mexoryl Helioplex J Am Acad Dermatol stable 2005;52:93 7-58
- 39. Sunscreen (physical) Active Ingredients • Titanium oxide • Zinc oxide stable
- 40. FDA guidelines
- 41. Fitzpatrick’s Skin Phototype Facultative pigmentation Constituitive pigmentation tan burn 1 2 3 4 5 6 library.thinkquest. org
- 43. Acral Lentiginous Melanoma • 70% of melanomas in darkly complected people, 45% of Asians • Still more common in light-complected • Hutchinson sign: extension of pigment into proximal or lateral nail fold
- 44. Melanoma incidence rates by ethnicity/race Incidence rates by Male (per 100,000 Female (per 100,000 race/ethnicity men) women) All races 23.6 14.9 White 27.2 14.9 Black 1.1 0.9 Asian/Pacific Islander 1.7 1.3 American Indian/Alaska 4.1 2.0 native Hispanic 4.5 4.6 Seer data 2000-2004 from 17 SEER geographic areas.
- 45. Melanoma death rates by ethnicity/race Death rates by Male (per 100,000 Female (per 100,000 race/ethnicity men) women) All races 3.9 /23.6 1.7 White 4.3 /27.2 2 Black 0.5 /1.1 0.4 Asian/Pacific Islander 0.4 /1.7 0.3 American 1.3 0.7 Indian/Alaska native Hispanic 0.9 0.6 Seer data 2000-2004 from 17 SEER geographic areas.
- 48. Diagnosing melanoma • Biopsy is performed removing entire lesion • Histopathology is read by dermatopathologist • Thickness • +/- ulceration • Number of mitoses
- 49. Breslow thickness – the most important prognostic factor
- 51. Pigmented lesion - improved software Improved clinical - non-invasive imaging detection Improved biologic -histologic markers markers to determine -blood markers biologic risk
- 52. Environmental Genetic •ultraviolet •skin color radiation •family history of • sunburns melanoma • # of moles •prior history of melanoma •immunosuppression •atypical nevi •lack of access •lack of education
- 53. Sun-exposed melanomas associated with increased number of genomic mutations Sun exposure
- 55. Pigmented lesion - improved software Improved clinical - non-invasive imaging detection Improved biologic -histologic markers markers to determine -blood markers biologic risk
- 56. • Stay out of sun (10 AM to 4 PM) • Wear sun protective clothing • Reapply sunscreen • Replenish your vitamin D
- 57. Environmental Genetic •ultraviolet radiation •skin color • sunburns •family history of melanoma • # of moles •prior history of •immunosuppressio n melanoma •atypical nevi •lack of access •lack of education
- 58. Immunosurveillance for skin cancer • Increased risk in the setting of immunosuppression • 65-250x more SCC • 10X more BCC • 8X more melanoma Rangwala S and Tsai KY. BJD. 165 (5): 953-65. Nov 2011.
- 59. Clinical presentation •55 yo WM •3 year h/o previously biopsied “freckle” on nasal tip
- 60. Pathology •LENTIGO MALIGNA, PRESENT AT MARGIN
- 62. Treatment options • Narrow margin excision • Radiotherapy • Topical immunomodulators
- 63. Imiquimod
- 64. 4 wks 10 wks BIW x 2 wks QD x 6 wks BID x 3 wks 5x/wk x 2 wks 24 wks 17 wks 13 wks QD x 4 wks QD x 4 wks none x 2 wks Photographs courtesy of Andrew Werchniak, MD
- 65. Results and follow-up •Clinical resolution of disease •Close follow-up q 3-6 months for years •Wood’s lamp •Dermoscopy •RCM •Surveillance biopsies
- 66. In-transit metastases QD x 2 wks QD x 4 wks
- 67. Clinical presentation • 47 yo bus driver • 6 month history of enlarging “callus” • In-transit metastases • Palpable inguinal LN • Restaging PET/CT: bilateral inguinal LAD & liver metastases
- 70. Clinical trials
- 72. Rapid, dramatic tumor shrinkage observed
- 74. Ipilimumab: CTLA-4 blockade T-cell activation T-cell inhibition T-cell potentiation T cell T cell T cell CTLA4 CTLA4 TCR X CTLA4 TCR TCR CD28 CD28 Antibody CD28 MHC B7 binds MHC B7 CD28 B7 MHC CTLA-4 APC APC APC Courtesy of Steve Hodi MD
- 75. Kaplan-Meier analysis of survival 1.0 lpi + gp100 0.9 lpi alone 0.8 gp100 alone Overall survival (%) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1 2 3 4 Time (years) Hodi et al, NEJM 2010.
- 76. Summary • Melanoma continues to increase in incidence. Protecting against ultraviolet radiation exposure is the current best preventative strategy. • We aggressively screen high risk patients for melanoma and educate on sun protection, skin cancer screenings. • We continue to look for improved detection techniques and biomarkers to detect melanoma at its early, curable stage • We are interested in boosting the immune system in patients who are already at higher risk of developing melanoma
- 77. Future directions • Determine the immune response that is capable of clearing early melanoma and improve our body’s natural immunosurveillance • Discover biomarkers in precursor melanoma lesions to predict biologic potential and risk
- 78. Acknowledgements Jeffrey Feingold
- 79. Thank you!
- 80. Q&A • Do you see more melanoma in the Sun Belt? • If you have a skin legion, how do you know if it is precancerous? And if you wanted it removed to be safe, will insurance companies cover it? 80
- 81. Q&A • Is any sun exposure okay? 81
- 82. Q&A • Is it true that women get more melanoma on their legs and men get more melanoma on their body (trunk)? • How do you know how fast a melanoma will grow? 82
- 83. Q&A • What percent of melanomas go on to become advanced cancers (Stage IV)? 83
- 84. Q&A • Does clothing provide sun protection? • And what about special SPF clothing? 84
- 85. Q&A • How do you know what level of SPF to buy? 85
- 86. Q&A • What role does Vitamin D play in health? • And if we can’t be in the sun, should we take a Vitamin D supplement? 86
- 87. For more information… Watch our YouTube video on preventing and identifying melanoma here: •http://www.youtube.com/watch?v=OXt-yXFq39w Visit the DFCI Melanoma Treatment Center website: •http://www.dana-farber.org/Adult-Care/Treatment-and-Support/Melanoma.aspx
Editor's Notes
- Hello to the entire DFCI community. It’s a real honor to kick off this series of lunch meetings which we hope will integrate the current knowledge that we are gathering and bring that information to our communities.
- Melanoma is a broad topic to overview, but some of our goals for today’s
- 1:50 Americans will be diagnosed with melanoma, lifetime risk of 2% for an American born today.
- How do we find that 1 out of 50 however in a state where the disease is curable?
- In looking at the SEER data (surveillance epidemiology and end results)
- How do we find that 1 out of 50 however in a state where the disease is curable?
- So for individuals who are at high risk genetically, we follow them closely.
- Source: NCI Visuals Online. Skin Cancer Foundation. http://visualsonline.cancer.gov/about.cfm The ABCDs of melanoma skin cancer are: Asymmetry. One half doesn't match the appearance of the other half. Border irregularity. The edges are ragged, notched, or blurred. Color. The color (pigmentation) is not uniform. Shades of tan, brown, and black are present. Dashes of red, white, and blue add to a mottled appearance. Diameter. The size of the mole is greater than 1/4 inch (6 mm), about the size of a pencil eraser. Any growth of a mole should be evaluated.
- These were the good old days, right? Being the coppertone girl?
- UVB (295-315) and UVA (315-400 nm)
- How about the individuals who are naturally more protected in the sun?
- How do we find that 1 out of 50 however in a state where the disease is curable?
- Treatment is usually surgery and we can essentially cure the patient.
- First, we know that no matter what, we would like to catch the disease early. Like other cancers, melanoma is a disease of progression, and our goal is to catch the lesion early when it is still in a treatable stage before it has the opportunity to invade. We also are understanding the molecular changes that allow these cells to change and develop new targetted therapy. Finally, we are learning how the immune system fights against cancer cells, and how we can boost the immune system.
- Our first patient is a . . . So this is a 55 yo man who is really more interested in treatment options than diagnosis of the lesion. The lesion has already been present for several years and has even been previously biopsied and treated.
- the patient was diagnosed with . . . . at the dfci, we consider lm a mis. evidence of progression, and/or recurrence rate In this case, we were fortunate to arrive at the diagnosis with the initial biopsy. Often multiple biopsies need to be taken if your suspicion is high but We tend to do multiple punch biopsies on suspicious lesions as areas of invasion may be focal. Where to take these biopsies may be enhanced by technology in the future.
- the standard of care for lm is wide local excision In out institution, lentigo maligna is treated as an in-situ lesion. The actual conversion rate has only been estimated based on histopathology. Excision is standard of care but this can be quite challenging. REcurrence rates of Mohs 3%, radiotherapy 7%
- treatment options included narrow margin excision and radiation therapy both of which our patient refused. accordingly, we explored the use of . . . .
- Imiquimod works as an agonist for toll-like receptor 7 to actigate dendritic cells and induces type I interferon. TLR7 is on the surface of dendritic cells, macrophages, neutrophils Th1 response is induced with upregulation of cytokines (IFNγ, IFNα, IL-12) and cytotoxic T-cell recruitment
- in our patient, we started with imiquimod 5 nights weekly. we noted a minimal inflammatory response at 6 weeks at which point we increased dosing to twice daily which results in a more brisk inflammatory response shown here at 8 weeks that was continued through 12 weeks of therapy. the results at 16 weeks are shown here. Initially started 2x/wk, then 5x week (up to 4 weeks), then QD, then finally BID and achieved a vigorous response. AFter 8 weeks, had vigorous response. Then did Q3D for 3 more weeks. Finally off aldara for 2 weeks. surveillance biopsies.
- Wood’s lamp. Epidermal pigmentation or loss of epidermal pigmentation is enhanced by wood’s lamp. Dermal pigmentation tends to disappear- also biopsy surveillance
- at this point, the patient presented to the dana farber where we noted local recurrence, in transit metastases, and palpable inguinal LNs Unfortunately, even in the setting of discussion of surgical options when we met her, there was rapidly progressing local recurrence and in-transit disease. STage IV disease was confirmed with evidence of involvement of lung, nodes, liver
- based on the presence of distant visceral organ metastases, the patient was diagnosed with stage IV mm. Stage IV melanoma has a 40% survival in the 1 st year.
- treatment options for stage IV MM include . . . . for the remainder of this talk, i will focus on these 2 exciting phase III agents
- 40-60% of melanomas have BRAFV600E mutations .
- Complete or partial regression seen in 80% of patients. Median progression free survival is 7 months
- starting with ipilimumab which works by ctla-4 blockade. ctla-4 (shown here) is a t cell receptor. binding of ctla-4 by the b7 ligand inhibits t cell activation. ipi is a ctla-4 antibody. ctla-4 blockage reverses t cell inhibition. activated t cells are thus free to fight cancer. Mechanism of action CTLA-4 enhances immunologic memory response
- shown in blue are patients treated with ipi. shown in orange are patients treatedw ith ipi and the vaccine gp100. shown in black are the patients treated with vaccine alone. patients treated with ipi had an improved os as compared with the other 2 groups Median overall survival of ipi + gp100 was 10 months compared to 10.1 months of ipi alone. Gp100 was 6 months
- Newer agents such as these give us hope that we can and will do better for our patients with metastatic melanoma n terms of therapies, only two drugs have been approved for melanoma in the U.S.: dacarbazine (DTIC) and high-dose interleukin-2, "neither of which work very well," Dr. Halpern said. Additional therapies for melanoma also include nitrosoureas, cisplatin, interfer-a, taxol, and vincristine, all with response rates under 20 percent. Only IL-2 actually results in melanoma cures. In terms of new therapies, one exciting development includes stem-cell targeted therapy. "Instead of killing the cancer cells in the tumor, kill the stem cells, and the tumor will die off on its own," he said. Another development includes a simplified scheme of targeting melanoma pathways, including mutations in cell cycle regulation. Disrupting any one of the mutations stalls the advancement of melanoma. One clinical trial of immunologic-checkpoint blockade agents showed that patients did not improve during the time frame the clinical trial was set — six to eight weeks. However, these patients started to improve three and four months later, requiring that the criteria for this trial change. By waiting longer, investigators found dramatically improved response rates — 40 percent to 50 percent, compared to 20 percent average response rates of other melanoma therapies. "There are other similar immune checkpoint molecules for which other drugs are being developed," Dr. Halpern noted. Return to Index
- Newer agents such as these give us hope that we can and will do better for our patients with metastatic melanoma n terms of therapies, only two drugs have been approved for melanoma in the U.S.: dacarbazine (DTIC) and high-dose interleukin-2, "neither of which work very well," Dr. Halpern said. Additional therapies for melanoma also include nitrosoureas, cisplatin, interfer-a, taxol, and vincristine, all with response rates under 20 percent. Only IL-2 actually results in melanoma cures. In terms of new therapies, one exciting development includes stem-cell targeted therapy. "Instead of killing the cancer cells in the tumor, kill the stem cells, and the tumor will die off on its own," he said. Another development includes a simplified scheme of targeting melanoma pathways, including mutations in cell cycle regulation. Disrupting any one of the mutations stalls the advancement of melanoma. One clinical trial of immunologic-checkpoint blockade agents showed that patients did not improve during the time frame the clinical trial was set — six to eight weeks. However, these patients started to improve three and four months later, requiring that the criteria for this trial change. By waiting longer, investigators found dramatically improved response rates — 40 percent to 50 percent, compared to 20 percent average response rates of other melanoma therapies. "There are other similar immune checkpoint molecules for which other drugs are being developed," Dr. Halpern noted. Return to Index