Karl D. Lewis, MD Associate Professor of Medicine University of Colorado Denver Cutaneous Oncology...
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Karl D. Lewis, MD Associate Professor of Medicine University of Colorado Denver Cutaneous Oncology Program Locally Advanced and Metastatic Basal Cell Carcinoma:
Karl D. Lewis, MD Associate Professor of Medicine University of
Colorado Denver Cutaneous Oncology Program Locally Advanced and
Metastatic Basal Cell Carcinoma: Medical Oncology Perspective
Slide 2
2 Basal Cell Carcinoma Arise from the keratinocytes of the
basal layer of the epidermis Generally have a low metastatic
potential However, can be locally aggressive with destruction of
skin and surrounding structures Most common skin cancer in US
Imprecise because no cancer registry ACS in 2000: ~975,000
cases
Slide 3
3 BCC - risk factors UV light exposure Sun exposure (habits) is
most important environmental factor (along with individuals
phenotype)
Slide 4
4 BCC - risk factors Basal Cell Nevus Syndrome Robert Gorlin
(dentist) identified a syndrome in which multiple abnormalities
occur 1. Autosomal dominant Prevalence varies from 1/57,000 to
1/256,000 Patients can develop hundreds of BCCs - usually starting
by age 35 Histologic appearance does not differ from sporadic BCCs
1. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine
1987;66:98-113.
Slide 5
5 Basal cell nevus syndrome Major Criteria Multiple BCCs or one
under 20 yrs Odontogenic keratocysts Palmar/plantar pits Bilamellar
calcification of the flax cerebri Bifid, fused or splayed ribs
Affected 1st degree relatives Minor Criteria Macrocephaly
Congenital malformations (eg, cleft lip) Ovarian fibroma Skeletal
abnormalities Medulloblastoma
Slide 6
6 palmer/plantar pitting Bone cysts (mandible) Bifid ribs
Slide 7
7 Basal Cell Nevus Syndrome (BCNS) Positional cloning and
subsequent screening identified a spectrum of PTCH mutations in
BCNS patients BCCs develop secondary to activation of target genes
of Hh pathway in cells that have lost both normal copies of
PTCH
Slide 8
8 Hedgehog Signaling Pathway Basal cell nevus syndrome:
Germline mutation in PTCH gene The hedgehog pathway is active
during embryonic development but dormant after birth
Slide 9
9 Sporadic BCCs Majority show allelic loss for chromosome 9q22
and inactivating mutations of PTCH Activating mutations of SMO in
10-20% sporadic BCCs Suggests abnormal Hh signaling involved in
most (all?) BCCs - high levels of Hh target genes such as GLI1
Slide 10
10 Basal Cell Carcinoma Treatment Low risk lesions: Cryosurgery
Electrodessication Topical therapy: 5-FU or imiquimod High risk
lesions: Surgical excision Mohs micrographic surgery Radiation
therapy (cure rates 85-95%)
Slide 11
11 Basal Cell Carcinoma Treatment Low risk lesions: Cryosurgery
Electrodessication Topical therapy: 5-FU or imiquimod High risk
lesions: Surgical excision Mohs micrographic surgery Radiation
therapy (cure rates 85-95%)
Slide 12
12 Medical Oncologist Role in Treatment of BCC Historically:
little to none No clinical trials demonstrating chemotherapy
benefit Chemotherapy responses on case-report basis only NCCN
Guidelines: recommend clinical trials (Hhi) for metastatic BCC
Slide 13
13 Medical Oncologist Role in Treatment of BCC Metastatic BCC
First case of metastatic BCC reported in 1894 1 Since then have
been >300 cases reported Accurate incidence difficult to obtain:
no good registry Estimated rates reported to be: 0.0028% to 0.55%
2,3 However, these data are old and based on single institutions or
small subsets The lower incidence would translate to 1 in 35,000
patients (seems too high considering total number of patients
reported in the literature) 4,5 1.Beadles DF. Trans Pathol Soc
1894. 2.Paver K et al Australas J Dermatol 1973 3.Cade S et al 1940
4.Wadhera A et al Dermatol Online J 2006 5.Ganti AK et al Cancer
Treat Rev 2011
Slide 14
14 Chemotherapy for BCC Metastatic Numerous agents on
case-report basis: Cyclophosphamide, etoposide, 5-FU, MTX,
bleomycin, doxorubicin, cisplatin, carboplatin, paclitaxel
Cisplatin (alone or combination) likely most effective: 12 patients
treated with platinum containing regimen 1 : 5 CR (3 to 18 months)
4 PR 3 SD 1. Carneiro BA et al Cancer Invest, 2006
Slide 15
15 Chemotherapy for BCC Problems with case-reports: No
consistent treatment regimen Dose Schedule Timing of response
Selection bias of patients What prompted treatment vs no treatment
Much more likely to report responders than non-responders No
standardization of response evaluation!!!! Even though chemo
responses seem encouraging it is not known what the true response
rate is.
Slide 16
16 BCC Since the HH pathway seems to be ubiquitously expressed
in BCC, there may be a potential for targeted therapy.
Slide 17
17 Cyclopamine Anomalous development due to disruption of
Hedgehog signaling Veratrum CalifornicumCyclopic lamb Enabled by
the ingenuity of Lynn James, from the US Department of Agriculture,
in investigating the curious case of an epidemic of cyclopic lambs
in Idaho, 1957
19 ERIVANCE BCC: Pivotal Phase 2 study in advanced BCC Locally
advanced BCC: Inoperable Surgery inappropriate 1 cm 2 recurrences
after surgery and curative resection unlikely and/or anticipated
substantial morbidity and/or deformity from surgery Metastatic BCC
(RECIST-measurable ) Locally advanced BCC REGISTRATION Progression
Intolerable toxicity Withdrawal from study RECIST Composite
endpoint Vismodegib 19 RECIST, Response Evaluation Criteria In
Solid Tumors
Slide 20
20 ERIVANCE BCC: Study Objectives Primary endpoint: Objective
response rate by independent review Hypotheses tested: Overall
response rate is significantly greater than 10% in patients with
mBCC or 20% in patients with laBCC Secondary endpoints included:
Objective response rate by investigator Progression-free survival
Duration of response Absence of residual BCC in patients with laBCC
20
Slide 21
21 Vismodegib demonstrates a significant objective response
rate in mBCC mBCC (n = 33) IRF (1)INV (2) Responders, n (%) Stable
disease, n (%) Progressive disease, n (%) Unevaluable/missing, n
(%) 10 (30.3) 21 (63.6) 1 (3.0) 15 (45.5) 2 (6.1) 1 (3.0) 95% CI
for objective response(15.6 48.2)(28.1 62.2) p-value0.0011 Median
duration of response, months7.612.9 21 CI, confidence interval;
IRF, independent review; INV, investigator review Sekulic A et al.
N Engl J Med. 2012;366:2171-2179.
Slide 22
22 Maximum decrease in tumor size by IRF Metastatic cohort 22
Change in lesion diameter (%) Partial response Stable disease
Progressive disease -100 -50 0 50 100 Maximum decrease in size
prior to IRF-determined disease progression Sekulic A et al. N Engl
J Med. 2012;366:2171-2179.
Slide 23
23 Vismodegib demonstrates a significant objective response
rate in laBCC laBCC (n = 63) IRF (1)INV (2) Responders, n (%)
Stable disease, n (%) Progressive disease, n (%)
Unevaluable/missing, n (%) 27 (42.9) 24 (38.1) 8 (12.7) 4 (6.3) 38
(60.3) 15 (23.8) 6 (9.5) 4 (6.3) 95% CI for objective response(30.5
56.0)(47.2 71.7) p-value