September 2015, Vol. 2, No. 5

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Molecular Biology of Cutaneous Malignancies Informs Clinical Practice

WCMC

Understanding the clinical presentations and molecular biology of cutaneous malignancies is essential to applying therapy to clinical practice. At the 2015 World Cutaneous Malignancies Congress, experts discussed contributors to the pathogenesis of melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, and Merkel cell carcinoma, including genetic drivers.

Melanoma

New concepts in melanoma from the dermatology perspective were presented by Suraj Venna, MD.

Downregulation of phosphodiesterase type 5 (PDE5A) contributes to the development of invasive melanoma; the use of the PDE5 inhibitor sildenafil was found to increase the risk of melanoma by 84% (JAMA Intern Med. 2014;174:964-970), and a filled prescription for any PDE5 inhibitor within 1 year prior to diagnosis increased the risk of malignant melanoma by 27% (JAMA. 2015;313:2449-2455). A prospective study with clearly defined inclusion and exclusion criteria with dosing is needed before altering current practice, said Venna, Medical Director of the Inova Melanoma and Skin Cancer Center, Fairfax, VA.

Higher caffeinated coffee intake was associated with a modest decrease in the risk of melanoma in a large US cohort (J Natl Cancer Inst. 2015;doi:10.1093/jnci/dju421), but advising high coffee intake is premature, he said.

Evidence from Germany suggests that nationwide skin cancer screening may lead to the prevention of a substantial proportion of melanoma deaths. Every opportunity should be used to screen patients with a complete skin examination, which takes 3 to 4 minutes, Venna urged. Patient detection of melanoma is reliable, he said, and reliance on nondermatologists for detection is encouraged.

Venna finished with a discussion of the selection of patients with thin melanomas for sentinel lymph node (SLN) biopsy. T1b melanoma is defined as a tumor thickness ≤1.0 mm with ulceration, or a mitotic rate ≥1/mm2. But not all T1b melanomas are created equal; there is a survival spectrum within this cohort. Very thin melanomas (0.01-0.50 mm) with a mitotic rate up to 1.99/mm2 have a 10-year survival rate of 97%; survival starts to drop with a mitotic rate ≥2/mm2. Therefore, “T1b is not an automatic recommendation for SLN biopsy,” he said. “When making a decision about SLN biopsy in T1 patients, we need to consider all the available clinical and pathological features.”

The National Comprehensive Cancer Network (NCCN) in 2015 says that no consensus exists regarding the significance of ulceration, mitotic rate, and lymphovascular invasion. The NCCN does not advise SLN biopsy for stage 1A or 1B melanomas ≤0.75 mm, but it can be considered case by case for stage 1A melanomas that are 0.76 to 1.0 mm and in those with uncertainty of microstaging. It should be discussed and offered to patients with stage 1B melanomas that are 0.76 to 1.0 mm with ulceration or an elevated mitotic rate.

Anticipate that molecular techniques to classify high versus low risk of metastases will happen, Venna said.

The progress made in the translation from basic science to the clinic in advanced melanoma has yielded 1-year survival that approaches 80% with some of the therapies. Overcoming drug resistance that eventually develops is required for further gains, said Roger S. Lo, MD, PhD, Associate Professor of Dermatology/Medicine and Molecular and Medical Pharmacology, Geffen School of Medicine at the University of California, Los Angeles.

Improvement in progression-free survival has been obtained by combining a selective BRAF inhibitor (dabrafenib) with a selective MAPK inhibitor (trametinib) versus dabrafenib monotherapy in patients with metastatic melanoma and BRAF V600E mutations.

Melanoma tumors under selection by MAPK inhibitor, however, more frequently evolve recurrent nongenomic (vs genetic) alterations. “A majority of these nongenomic alterations are tumor cell intrinsic, induced by the MAPK inhibitor, and epigenetically based, with recurrent alterations in the DNA methylome,” said Lo. Intratumoral immunity then coevolves with the tumor compartment.

Acquired resistance and clonal evolution in melanoma during BRAF inhibitor treatment is bringing about an era of rational combinations and sequential therapies for BRAF-mutant tumors and BRAF wild-type tumors. Rational combinations being tested involve the addition of MEK inhibition, Akt inhibition, ERK inhibition, and pan-RAF inhibition to BRAF inhibition, or cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) inhibitor combinations, plus other novel kinase inhibitors and immune modulatory agents, in BRAF-mutant melanoma. In BRAF wild-type melanoma, inhibition by combinations of MEK, PD-1 or its ligand PD-L1, and anti–CTLA-4 therapies are being tested.

Basal Cell Carcinoma

Uncontrolled activation of the Hedgehog pathway is sufficient for basal cell carcinoma (BCC) development in mice, pointing to a pivotal role of this pathway in human BCC, said Christopher Bichakjian, MD. In fact, abnormalities in the Hedgehog pathway are detected in approximately 100% of patients with BCC.

Mutations in the PATCHED1 gene (PTCH1) have been identified in patients with nevoid BCC syndrome (Gorlin syndrome), and PTCH1 mutations have also been found in sporadic BCCs. PTCH1 is a receptor for sonic Hedgehog; this pathway is deeply involved in embryonic development by controlling proliferation, differentiation, and cell fate, explained Bichakjian, Clinical Associate Professor, Cutaneous Surgery and Oncology, University of Michigan Health System, Ann Arbor.

BCC demonstrates heterogeneous molecular progression resulting in various subtypes, all of which have the Hedgehog pathway mutation, said Steven A. Nelson, MD, Assistant Professor of Dermatology and Dermatopathology, Mayo Clinic, Scottsdale, AZ.

“We’re learning that there may be a molecular evolution in the profile of some of the subtypes,” he said. For example, metatypical BCC has a squamous cell carcinoma–like gene expression profile with increased immune response and oxidative stress-related genes. Other subtypes are infiltrative/morpheaform BCC, with increased levels of transforming growth factor-beta (TGF-β) and alpha-smooth muscle actin; micronodular BCC, with high p53 expression; superficial BCC, which has the fewest aberrations on gene expression profile; and fibroepithelioma of Pinkus type, which has minimal chromosomal aberrations compare with BCC by comparative genomic hybridization array.

Overexpression of p53 is seen in aggressive subtypes, said Nelson, and “might contribute to the Hedgehog pathway in a synergistic manner.” BCC with both a PATCHED mutation and a p53 mutation is considered a particularly aggressive subtype. CXCR4 expression also enhances invasion and angiogenesis, and increased FOXM1 correlates with aggressive growth.

The advent of Hedgehog pathway–targeting agents is changing the treatment approach to BCC, said Nelson. These agents include the already approved vismodegib and sonidegib, which are small molecule inhibitors of Smoothened. Additional Smoothened inhibitors are saridegib, taladegib, and itraconazole. Direct and indirect glioma-associated oncogene inhibitors are also under study.

Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of neoplasms of skin-homing T cells that includes mycosis fungoides (MF), which is the most common; Sézary syndrome (SS), the leukemia variant of MF; and other variants of CTCL.

Early CTCL cells thrive in an inflammatory environment, are functionally active, and display subtle deviation from normal T cells, said Joan Guitart, MD, Director of the Dermatopathology Unit, Northwestern University Feinberg School of Medicine, Chicago, IL.

CTCL is characterized by malignant clonal proliferations of skin T-cell subsets, such as resident memory T cells, central memory T cells, and T regulatory cells. A dominant clonal T-cell population in skin lesions is an important clue in the diagnosis of CTCL, and a dominant clone in the skin and blood, or on more than 1 site, is confirmatory of CTCL.

“We’re also learning that, parallel to what we learned earlier from melanomas, that often patients with CTCL have dormant or small subclones,” said Guitart. About 50% of patients with SS have 2 to 3 stable unreported T-cell receptor (TCR) subclones. T-cell subclones are involved with recurrence and treatment resistance.

“We are now starting to look at T-cell clonality with next-generation sequencing (NGS) with amplification of all the top clones. We can even sequence the T-cell receptor of the most dominant clones,” he said. “The new techniques of NGS give you a good idea of the repertoire of T cells, and they let you identify the dominant clones; you can track minimal residual disease, you can define the repertoire of the malignant clone, and perhaps in the future may help us find some specific etiologies.”

MF is a malignancy of mature, primed CD4+ T helper cells. They express CD45RO and the homing antigens, CLA/CCR4, and they depend on antigen-presenting cells (APCs) in the dermis and Langerhans cells in the epidermis. Those cells do not survive unless they are in close proximity to the APCs.

The malignant cells in MF have constitutive TCR activation. Mutations on CD28 are also present. An increase in CTLA-4 increases adhesion of normal cells to APCs. Patients have a T helper cell type 2 (Th2) cytokine profile with increased TGF-β secretion that recruit more immature APCs. With interleukin-10, they remain immature and cannot mount an immune response against the tumor cells.

Chronic antigenic stimulation is a feature of early MF, and it persists, but the nature of the stimulus is not known, said Guitart. “We don’t know what’s driving the chronic inflammation that’s often preceding MF,” he said. In addition to TCR activation, defects in apoptosis lead to early T-cell clones.

The cell-mediated immune system plays an important role in the progress of CTCL. The disease worsens with immune suppression, and response to immunotherapy is good. The number of circulating CD8+ cells correlates with prognosis at all stages.

“At the same time, CTCL cells are highly immunogenic,” said Guitart. CTCL is an immune-suppressive disease, with overexpression of Th2 genes, a Th2 cytokine profile, and marked depletion of T-cell repertoire.

There is a lack of consensus on genomic drivers in CTCL, but several distinct molecular defects have been identified. DNA/microRNA array analyses show several heterogeneous somatic alterations in most cases. In advanced disease, common gains in chromosomes 8q (MYC) and 17q and losses in 1p, 9p (CDK-N2A), 10q (PTEN), 13q and 17p (TP53) are observed. Mutations in TCRs, including CTLA-4, have been identified in advanced MF/SS, opening the door to potential treatment with ipilimumab or bortezomib. Other common mutations have been seen in neoantigens and the STAT3/JAK pathway, among other pathways.

Merkel Cell Carcinoma

Immune mechanisms are implicated in the development of Merkel cell carcinoma (MCC), with reports that immune modulation can result in tumor regression.

The concept of an unknown primary tumor in MCC has important prognostic implications. The impact of an unknown primary lesion in stage IIIb MCC (palpable nodal disease) is large, with a near doubling of 5-year MCC-specific survival and overall survival with an unknown primary versus known primary lesion. This observation is consistent across different independent cohorts, said Paul Nghiem, MD, PhD.

The hypothesis for this phenomenon is that with unknown primaries in stage IIIb, functional killer T cells secrete effector cytokines or molecules that destroy the primary tumors. “What we think is going on is basically an immune phenomenon,” said Nghiem, Professor and Head, Division of Dermatology, University of Washington, Seattle. “The hypothesis would be if you don’t have good immune cell function you’re not going to be able to eliminate the primary tumor.”

In unpublished data, among stage IIIb MCC patients, 0 of 11 patients with a suppressed immune system eliminated the primary tumor, compared with 66% of the 92 stage IIIb patients who were not immune suppressed.

Given the links to immune suppression, it’s not surprising that a polyomavirus—Merkel cell polyomavirus (MCPyV)—has been found to give rise to MCC in about 80% of cases, said Nghiem. MCPyV is extremely common in normal skin, yet only 1 in 3000 people develop MCC over their lifetime.

Two things must happen to develop MCC, and both are more likely with ultraviolet exposure. The virus integrates into the chromosome at a defined site followed immediately by the occurrence of a second mutation. “If the oncoprotein is not chopped in half by a second mutation, there will be hundreds of copies of DNA made at this one site, and the cell will be killed,” he said. As part of the perfect storm, “the immune system then has to be duped.”

If the number of CD8+ T cells is moderate or high within the MCC tumor, survival was 100% in 2 independent cohorts of about 150 patients each.

Small and large T antigens are involved in a panoply of pathways in MCC, said Jaehyuk Choi, MD, PhD, Assistant Professor of Dermatology, Yale School of Medicine, New Haven, CT.

Small T antigens are involved in a number of pathways that affect protein homeostasis, specifically expression of pro-oncogenic proteins. Large T antigens increase T-cell proliferation and affect canonical tumor suppressor pathways such as RB1. Large T antigens increase survivin by increasing gene transcription, and thereby resist cell death, whereas loss of survivin kills MCPyV-positive MCCs.

Multiple pathways are dysregulated in MCC. Overexpression of targetable receptor tyrosine kinases has been suggested. The Akt/PI3K pathway is known to be activated in 88% of MCCs, although the mechanism for this activation is not clear, said Choi. MCCs express somatostatin receptors, which might lead to “Trojan horse” therapies or somatostatin analogs given alone or paired with a deadly payload such as a radioactive isotope, he said.

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Immuno-Oncology Brings New Opportunities for Developers of Targeted Cytotoxics

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