December 2014, Vol 3, No 8
World Cutaneous Malignancies Congress
The Third Annual World Cutaneous Malignancies Congress (WCMC) took place in San Francisco, California, on October 29-31, 2014. The WCMC is a 2-day meeting dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies. Following are highlights of presentations from the meeting.
Panel Considers Role of Conventional Treatment in Cutaneous Malignancies in Era of Targeted Therapy
Is there still a role for conventional therapies for cutaneous malignancies in the era of targeted agents? This was the question put before a panel of oncologic experts convened at the conference.
In Merkel cell carcinoma (MCC), conventional treatment for local and regional disease is effective, said Paul Nghiem, MD, PhD, professor of medicine, dermatology, and pathology, University of Washington, Seattle. “Without too much morbidity, we can render almost 100% of our patients free of detectable disease,” he said.
In contrast, treatment of MCC in the adjuvant setting is open to debate. “We have patients with nodal disease who have a 70% chance of dying of this cancer in a few years, yet they have no evidence of disease clinically,” said Nghiem. “This is the perfect setting to ask that adjuvant question.” In Europe, ipilimumab is being tried in this setting, he noted.
Conventional therapy for metastatic disease is a huge area of need, he said, as the response to chemotherapy in this setting is not durable. “You’re suppressing the immune system and making those cancer cells really angry. When they come back, they’re really hard to deal with,” he said.
In basal cell carcinoma (BCC), “we can be satisfied to say that targeted therapy is the only way to go for advanced disease. There’s not much argument there,” said Sanjiv S. Agarwala, MD, chief of oncology and hematology, St. Luke’s Cancer Center, Bethlehem, PA. Vismodegib is an oral agent approved for the treatment of adult patients with BCC that has metastasized or recurred after surgery, in addition to patients whose tumors are deemed untreatable with surgery or radiation.
Patients who desire the oral drug in lieu of conventional surgery or radiation therapy represent a dilemma for healthcare systems, said Axel Hauschild, MD, head of the Skin Cancer Center at the University of Kiel, Germany. “Ethically, does the community need to pay for those patients not willing to be operated on, although the oral drug is indicated after surgery?” he asked.
No targeted therapy exists for the management of cutaneous T-cell lymphoma (CTCL), with the exception of alemtuzumab for Sézary syndrome. The therapeutic window for alemtuzumab in Sézary syndrome is relatively narrow because of its immunosuppressive side effects, said Pierluigi Porcu, MD, associate professor of internal medicine, Division of Hematology, The Ohio State University, Columbus.
“Otherwise, CTCL essentially is a chronic disease for which patients stay on therapy for a greater part of their lives. The additional component is that there is a tendency to overlay different therapies as we go along,” said Porcu. Every patient who starts treatment of early-stage CTCL will receive a series of therapies that include a variety of topical agents and eventually phototherapy when the level of skin involvement becomes significant despite the topicals.
The key question, said Porcu, is when to add systemic therapy in CTCL. “In the past, the question was moot because the systemic therapies we had were relatively ineffective and certainly toxic,” he said. The discussion became more relevant with the introduction of bexarotene and, more recently, histone deacetylase (HDAC) inhibitors.
After phototherapy, “do you still go with bexarotene as your first agent or do you start using the new HDAC inhibitors?” he asked. The mechanisms of action of retinoids in CTCL must be better understood to make this decision, he believes.
“Moving down the road as far as disease severity, we don’t have a good way of debulking patients with advanced CTCL and taking them potentially to reduced-intensity stem cell therapy transplantation,” said Porcu.
The role of conventional treatments in metastatic melanoma seems to be dependent on the health system. In Germany, where ipilimumab is not reimbursed as first-line therapy, many patients with melanoma are treated with dacarbazine, said Hauschild. “If ipilimumab were available as first-line therapy, I would favor ipilimumab over dacarbazine,” he said. “There are some patients with clear contraindications, such as diverticulitis and other underlying autoimmune diseases, that preclude treatment with anti–CTLA-4 antibodies.”
“In France, it’s even worse because ipilimumab is not reimbursed for the BRAF-mutant patient,” said Caroline Robert, MD, PhD, head of dermatology, Institut Gustave Roussy, Paris. “If I had the choice, I would favor giving ipilimumab first line most of the time in BRAF wild-type and sometimes in BRAF mutant patients as well.”
In the future, clinicians may have the choice of an anti–PD-1 antibody, ipilimumab, or the combination of the 2 as first-line therapy. The choice then would depend on the magnitude of the benefit with the combination, Robert and Hauschild agreed. A survival rate of 80% to 90% with no grade V adverse events would tip the scale toward combination treatment, said Robert.
If combination therapy vastly improves overall survival, the toxicity would be little consideration given that treatment duration would be short, said Hauschild. “Maybe some people need just 2, 3, or 4 infusions and the job is done,” he said.
Knowledge of Biology of Malignant Melanoma Is Informing Treatment
An understanding of the molecular biology and genetics of melanoma is now integrated into the management of patients with this disease. Knowledge of the oncogenic driver mutations has allowed the development of targeted therapies, said Antoni Ribas, MD, PhD, director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center at the University of California Los Angeles.
Genomic studies have identified several targetable oncogenes in melanoma, in particular the protein kinase BRAF. The BRAF V600E mutation is the most common point mutation in melanoma.
Resistance occurs because in two-thirds to three-fourths of cases, the tumor finds a way to reactivate the MAPK pathway by increasing oncogenic signaling, either by amplifying BRAF or through alternate splicing that reactivates the kinase, or by allowing the copresence of a mutation of RAS and BRAF.
Genomic studies have also allowed uncovering of the major mechanisms of acquired resistance to BRAF inhibitors. Mutually exclusive mechanisms of resistance to single-agent BRAF inhibitors such as secondary RAS mutations, BRAF alternative splicing, BRAF amplification, or PTEN deletions have been described, said Ribas. “This mutual exclusivity is not in 1 patient; it’s in 1 lesion or another,” he said. “The melanoma finds ways to progress, and one lesion may progress differently from another one.” In this way, a branched evolution underlies acquired BRAF inhibitor resistance, and the tumors are finding different ways to escape.
“This tells us that we shouldn’t be chasing resistance; we should be anticipating resistance,” he said. The clinical data are progressing more rapidly than the ability to understand the rationale behind successful approaches to target resistance, such as up-front treatment with BRAF inhibition combined with MEK inhibition as a superior strategy to BRAF inhibition alone. Combination therapy is proving to improve initial responses and provide more durable responses and better overall survival.
An unanticipated benefit to double oncogenic pathway inhibition (BRAF and MEK) is the reduction in toxicities from paradoxical MAPK activation by blocking BRAF alone, in which blockade of BRAF within a dimer with CRAF results in increased MAPK signaling through the paradoxical transactivation of CRAF.
This paradigm described above can be used to treat RAS-driven melanoma, which preferentially signals through MAPK, he said. No RAS inhibitors have been developed so far, but blockade at the cell proliferation step – CDK 4/6 – has been shown in a phase 1b/2 trial to induce early tumor shrinkage when administered with a MEK inhibitor in NRAS-mutant melanoma, although duration of response has been short.
Genetics are also becoming important in the understanding of immunotherapy in melanoma. Patients with melanoma who have vast mutational heterogeneity may actually be easier to treat, Ribas explained, because their immune systems may be better able to differentiate the cancer cell from the normal cell, but the immune system is being blocked by PD-1. The antitumor activity of PD-1/PD-L1–blocking antibodies is likely to be related to immunogenic epitopes derived from genomic mutations.
Treatment Algorithm in the United States: Current and Future
Ribas followed with a discussion of current approaches to therapy in malignant melanoma in the United States. The treatment algorithm for advanced melanoma hinges on BRAF mutation; in BRAF-positive patients, options include anti–CTLA-4 therapy with ipilimumab or the combination of a BRAF and MEK inhibitor. High-dose interleukin (IL)-2 is also approved for this indication and is associated with a durable response in a subset of patients, but “it’s hard to advocate for high-dose IL-2 when you talk to a patient because it has not been tested in a randomized trial, it’s inpatient therapy, and it’s more toxic, at least in the short term,” he said. Patients who progress on these therapies are candidates for pembrolizumab, recently approved for the treatment of advanced melanoma in patients who have previously received a BRAF inhibitor.
In BRAF-negative patients, the thinking is the same but without the option of a BRAF inhibitor. “My first option is to offer ipilimumab and discuss the pros and cons,” he said.
“This is not how we’re going to be treating melanoma in 1 or 2 years, I would assume,” he said. “In 1 or 2 years, we’re going to be diagnosing melanoma based on the interaction between the cancer cell and the immune system.” The future approach will involve detecting a T cell that recognizes the cancer and leads to the production of interferon, one of the signaling molecules used by the immune system to attract other cells that can attack the target after specific recognition of antigen. The same signal leads to the expression of brakes that limit the immune response, and interferons lead to the expression of PD-L1. “If there’s PD-L1 and no T cells, it doesn’t matter if we block PD-1 or PD-L1. The effector cells are the immune system cells,” said Ribas.
The initial decision will depend on predictive factors for response to PD-1/PD-L1 blockade. If factors (T cells) are present, single-agent PD-1 or PD-L1 will be initiated. If features likely for response are present and the response is mixed or progression of disease occurs eventually, delayed combination therapy may be tried. If predictive factors are not present, combination therapy may be tried up front.
The Perspective From Europe
Hauschild explained systemic treatment approaches for advanced metastatic melanoma in Europe. The reimbursement mechanism is different across Europe, where treatment is price sensitive and the availability of new drugs may be limited.
Recent approvals for melanoma in Europe include ipilimumab (reimbursed primarily for second-line treatment), and the BRAF inhibitors vemurafenib and dabrafenib (single-agent approval). IL-2 has never made it to the market in Europe for the treatment of melanoma.
“In France, ipilimumab is approved but only reimbursed for patients not carrying a BRAF mutation,” he said. “There is zero scientific evidence for this. The BRAF-mutated patients should be referred for targeted therapy since they have no opportunity for ipilimumab. This is in the interest of money; the questions in Europe are circulating around reimbursement of these drugs.”
The European Medicines Agency seeks phase 3 trials that must demonstrate at least an advantage in progression-free survival, “but they are more likely to accept an overall survival improvement, and it must be clinically meaningful,” he said.
ESMO developed a guideline for screening, early detection, treatment of the various stages of melanoma, and follow-up, but it is only 2 pages and therefore weak, believes Hauschild.
The new German guideline is based on a Cochrane review of the existing literature, involves 32 disciplines from the German Cancer Society in a complex consensus process, and is updated annually. The current German guideline recommends evaluating BRAF mutations from stage IIIB+ melanoma. “This means that we are not waiting for stage IV disease, because stage IIIB and IIIC have a bad prognosis, and very many of them will progress to stage IV,” he said. If the patient is BRAF-negative, it is recommended that the pathologist test for NRAS mutation. Only 1% of melanomas in Europe carry cKIT mutations, so it can be neglected.
In “triple-negative” melanoma (negative for BRAF/NRAS/cKIT), the first choice is referral to a clinical trial. Other options are single-agent chemotherapy or polychemotherapy.
If the tumor load is low and the disease is progressing slowly, first choice is referral to a clinical trial, with single-agent chemotherapy (dacarbazine) or ipilimumab as options. With progressive disease at this point, ipilimumab is an option, as is monochemotherapy.
For patients carrying a BRAF mutation and a high tumor load and rapidly progressive disease, “there is no doubt that they should be referred to BRAF inhibition,” either in combination with a MEK inhibitor or as a single-agent BRAF inhibitor, he said.
The time to response is important in the decision, as anti–CTLA-4 antibody treatment requires time to work, whereas targeted therapies work quickly.
In general, a high tumor burden, symptomatic disease, and a high level of lactate dehydrogenase favors combination treatment “because treatment outcomes, in terms of response rate induction, are very good, and also the time to best response is very fast,” said Hauschild.
Molecular Understanding of BCC Leads to Effective Targeted Therapy
Hedgehog pathway activation is instrumental for initiation and maintenance of BCC. The understanding of the molecular basis of BCC has led to the advent of Hedgehog pathway–targeting agents that are changing the approach to the treatment of BCC, said presenters at the conference.
The majority of BCCs develop through altered activation of the Hedgehog signaling pathway. Its origins were described by James Macdonald, MD, dermatologist at Central Utah Clinic in Provo.
The Hedgehog pathway was originally described in embryonic development and controls proliferation, differentiation, and apoptosis. This pathway was first linked to cancer when a mutation in the transmembrane receptor protein PTCH was found to cause Gorlin syndrome.
In the resting state, PTCH acts to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction. Stoichiometric binding of the Hedgehog ligand to PTCH releases inhibition of Smo, which serves to activate transcription factors (Gli1, Gli2), cell proliferation genes (cyclin D, cyclin E, Myc), and regulators of angiogenesis. “The balance of PTCH (inhibition) and Smo (activation) therefore manages the essential regulatory downstream Hedgehog signal transduction pathway,” said Macdonald. “Loss-of-function mutations of PTCH or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.”
BCC demonstrates heterogeneous molecular progression, resulting in various subtypes of the disease:
- Molecularly, metatypical BCC shares the most features with squamous metaplasia. For example, compared with other subtypes of BCC, metatypical forms express high levels of immune-response genes such as ß-catenin and CXCR4
- Infiltrative forms of BCC are often embedded in a sclerotic stroma, in keeping with the molecular finding of high levels of profibrotic cytokines (ie, transforming growth factor-beta) and fibroblastic markers (ie, alpha-SMA)
- Micronodular forms highly express altered p53 protein
- Superficial BCC is the least molecularly complex, with the fewest aberrations on gene expression profile
- Fibroepithelioma of Pinkus type has minimal chromosomal aberrations compared with BCC
Overexpression of p53 is observed in aggressive BCC subtypes. Mutations of p53 occur in as many as half of BCCs, with most of these mutations being UV signature mutations. A particularly aggressive subtype of BCC has both Smo mutation and p53 mutation.
In the different BCC subtypes, driver mutations are similar and occur predominantly through the Hedgehog signaling pathway. With the ubiquitous expression of the Hedgehog pathway in BCC, therapy targeting this pathway is logical, said Karl D. Lewis, MD, associate director, Melanoma Research Clinics, University of Colorado Denver.
“Hedgehog inhibitors have demonstrated high activity as well as durability in advanced BCC,” he said. “They have a predictable toxicity profile, and that toxicity profile does make it difficult for patients to maintain on these drugs long-term.”
The first agent that acts on the Hedgehog pathway to be approved for the treatment of advanced BCC is vismodegib. Erivance BCC was a pivotal phase 2 study that included patients with metastatic BCC measurable by imaging and locally advanced BCC (N Engl J Med. 2012;366:2171-2179). Patients with metastatic BCC or patients with locally advanced BCC who had inoperable disease or for whom surgery was inappropriate were treated with vismodegib 150 mg/day until disease progression, intolerable toxicity, or withdrawal from study for other reasons. Responses in the metastatic cohort were measured by imaging using RECIST criteria, and in the locally advanced cohort using a novel composite end point that included measurable diameter and ulceration of visible tumor as well as RECIST measures of the deeper tumor component when present.
The objective response rate (ORR) in the 33 patients with metastatic BCC was 30% as measured by independent review (P=.001) and 46% by the investigators. Another 64% of patients had stable disease, and progression as best response was observed in only 3% of patients.
In the 63 patients with locally advanced BCC, the ORR was 43% as measured by independent review (P<.001) and 60% by the investigators, with complete response in 13 patients (21%). Another 38.1% of patients had stable disease, with progression in 12.7% of patients. “Of relevance, the response rate observed by investigators in this study is identical to that observed by investigators in the phase 1 study,” said Lewis. “Clinical response to vismodegib observed in responders frequently occurred in a matter of weeks.”
A second agent that blocks Hedgehog activity is the selective Smo inhibitor sonidegib. Updated results from the BOLT study of sonidegib in patients with metastatic or locally advanced BCC were presented at the 2014 ESMO. The randomized phase 2 study was conducted in 230 patients with locally advanced (n=194) or metastatic (n=36) BCC who were randomized in a 1:2 fashion to 200 or 800 mg/day of sonidegib. “It met its primary end point of objective response rate of >30% after a median follow-up of 13.9 months,” said Lewis.
The updated results presented at ESMO were from a median follow-up of 20 months, at which time the ORR in the 200-mg/day cohort in patients with locally advanced BCC improved from 47% (primary analysis) to 58% (12 months), and from 35% (primary analysis) to 44% (12 months) in the 800-mg/day cohort.
In the group with metastatic BCC, the ORR dropped from 15% (primary analysis) to 8% (12 months) in the 200-mg/day cohort because a patient initially deemed to have a partial response was subsequently deemed to have stable disease, and was maintained at 17% in the patients assigned to 800 mg/day. The disease control rates were high, at about 90%, in both dosage groups.
The main adverse events were predictable – muscle spasms, alopecia, dysgeusia, nausea, fatigue, and weight loss. About 30% of patients had elevations in creatine kinase. The dose of sonidegib likely to go forward is 200 mg/day based on the better benefit-risk profile, said Lewis. “It’s my understanding that they’re trying for first-line approval,” he said. “Which one you’ll use up front is unknown at this point in time.”
He said that both vismodegib and sonidegib probably impact the natural history of locally advanced BCC, although this remains to be proved. Alternate targets in the Hedgehog pathway, perhaps Gli, and targets outside of this pathway are still needed for patients who lack a complete response on Hedgehog inhibitors or who have disease progression.
Treatment Algorithms for CTCL Reflect Involvement of Different T-Cell Subsets
Overexpression of IL-15 has a causal role in the pathogenesis of CTCL, which displays response to inhibitors of HDAC. The anti-CD52 antibody alemtuzumab effectively treats leukemic CTCL without compromising the immune response to infection.
These were themes discussed during the congress.
IL-15 Overexpression Induces CTCL
CTCL describes a group of heterogeneous diseases derived from skin-homing T cells. Malignant T cells of the CD4 phenotype target and persist in the skin but also accumulate in the lymph nodes and peripheral blood with disease progression.
IL-15 is a potent stimulant and growth factor for CTCL cells. Analysis of malignant CD4+ T cells demonstrates overexpression of IL-15 in patients with CTCL, said Anjali Mishra, PhD, assistant professor at The Ohio State University Comprehensive Cancer Center, Columbus. In patients with CTCL, the increase in IL-15 transcript is directly proportional to disease severity.
“IL-15 transgenic mice progress to a severe stage of CTCL, as characterized by extensive patch/plaque skin lesions, progressive alopecia, and severe pruritus within 6 weeks of birth,” said Mishra.
Adult IL-15 transgenic mice develop extensive involvement with cutaneous lymphoma causing fatality. Antibodies staining of CTCL mice reveal expression of CD3+CD62L–CD44hiCCR4+CLA+. Further, lymphoma cells from IL-15 transgenic mouse skin engrafted and mimicked the primary disease in immunodeficient mice upon adoptive transfer.
Epigenetic Events in CTCL
CD4+ T cells from CTCL patients show high expression of HDAC1, HDAC2, and HDAC6 transcripts. Using specific HDAC inhibition to target HDAC1/2 and/or HDAC6 in IL-15 transgenic mice was able to prevent clinical disease, said Mishra, whereas IL-15 transgenic mice receiving placebo progressively developed lesions during the course of treatment. The data suggest that “inhibiting HDAC1, HDAC2, and/or HDAC6 pathways inhibits the development of CTCL in IL-15 transgenic mice,” she said.
A novel pan-HDAC inhibitor can reverse severe dermatologic disease in the CTCL model. Histopathologic analysis of IL-15 transgenic mice treated with a pan-HDAC inhibitor (AR42) showed clearance of CD3+ and CD4+ atypical lymphocytic infiltrate compared with mice that received placebo.
Treatment Options in CTCL
The 2 most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. A staging system implies a uniform transition from mycosis fungoides to Sézary syndrome, but this staging system does not accurately portray the natural history of disease. In addition, criteria used to define blood and lymph node involvement vary according to the study. “The exact risk of stage progression is not very well known,” said Porcu. “The risk could be as low as 10% to 15% or as high as 25% to 40%.”
Treatment of CTCL is dependent upon the stage at diagnosis. The 2 categories of treatment are skin-directed and systemic therapies. The effect of treatment on stage progression and survival in CTCL is not known. Approved systemic agents for the treatment of CTCL are romidepsin, an HDAC inhibitor; denileukin diftitox, a fusion protein; bexarotene, a retinoid; and vorinostat, another HDAC inhibitor.
Some agents have been approved with restrictive indications. For example, denileukin diftitox is approved specifically for a subset of patients with tumors that express CD25, and bexarotene and vorinostat are approved specifically for the skin manifestation of CTCL.
Of the HDAC inhibitors, vorinostat is approved for the treatment of cutaneous manifestations in patients with CTCL who have progressive, persistent, or recurrent disease on or following 2 systemic therapies, and romidepsin is approved for the treatment of CTCL in patients who have received at least 1 prior systemic therapy.
The response rates for these agents are approximately 30%, and the durations of response range from 4 to 6+ months (a high of 15 months in the pivotal trial of romidepsin). Response to romidepsin is observed across all stages of disease.
“The overall management of CTCL across the stages is complex,” said Porcu. “It requires a coordination of care between medical, oncology, and dermatology. There is no unified standard of care. The closest thing to standard of care is HDAC inhibitors in Sézary syndrome.”
Immunology of Malignant T Cells
Diverse populations of T cells are found in human skin and blood, and all of them can undergo malignant transformation. Human skin is populated by a combination of resident memory T cells and recirculating memory T cells.
Resident memory T cells don’t recirculate; they make copious amounts of inflammatory cytokines, are highly protective locally, and accumulate in barrier tissues. “Resident memory T cells persist, protect, and they stay put,” said Rachael A. Clark, MD, PhD. Central memory T cells, by virtue of their expression of L-selectin and CCR7, can gain access to the lymph nodes. Central memory T cells recirculate between the blood and the lymph nodes.
Previously thought to be different stages of the disease, recent evidence shows that mycosis fungoides and Sézary syndrome represent lymphomas derived from these different T-cell subsets. Leukemic CTCL is a malignancy of central memory T cells, whereas mycosis fungoides is a malignancy of skin resident effector memory T cells.
“If you know that the malignant T cell that is responsible for the disease is skin resident and nonrecirculating, then local therapies can be a possible cure,” said Clark, associate professor, Department of Dermatology, Harvard Medical School, Boston, MA. In fact, very low-dose radiation therapy reduces malignant T-cell clones by 90% and maintains benign T-cell populations in patients with mycosis fungoides.
The story is different in leukemic CTCL because memory T cells recirculate. Alemtuzumab is a humanized anti-CD52 antibody that rapidly depletes all T and B cells from blood. At low doses, alemtuzumab induces partial response in 100% or complete response in 50% of patients with refractory leukemic CTCL. “To put this in perspective, vorinostat and the other systemic therapies are only partially effective in 30% of patients,” she said.
“We biopsied the skin of patients on alemtuzumab and found that healthy, benign T cells were present in the skin after alemtuzumab, but the malignant clone was missing after alemtuzumab, as was the population of normal central memory cells,” she said. “It turns out that alemtuzumab depletes in only 1 specific way: by antibody-dependent cellular cytotoxicity.” T-cell depletion with alemtuzumab requires the presence of neutrophils, a cell type frequent in blood but rare in normal skin.
The findings suggest that central memory T cells were depleted because they recirculate between the blood and the skin, whereas skin resident T cells were spared because they are sessile and don’t recirculate.
In addition, despite the absence of T cells in the blood, there was a marked lack of infections in alemtuzumab-treated leukemic CTCL patients, “which suggests that skin resident T cells can protect the skin from pathogens even in the absence of T-cell recruitment from the circulation,” she said.
Critical lessons about the human immune system were learned from this research. “The population of cells that don’t recirculate can provide a lot of immune protection, even in the complete absence of circulating B and T cells,” she said. Also, there are some central memory T cells that recirculate, as in the case of Sézary syndrome, which are the malignant cell type.
CTCL Therapies on the Horizon
Desirable features of systemic therapy in CTCL are response rates ?30%, favorable toxicity, an impact on symptoms (itching), an improvement in time to progression or time to next therapy, a favorable schedule of administration, competitive cost, avoidance of the need for IV catheters, preservation or restoration of immune competence, activity across all anatomic components, and few drug-drug interactions.
There are several promising new therapeutic approaches in the management of CTCLs, said Porcu. The JAK/STAT signaling pathway has been found to harbor somatic mutations in human CTCL, opening the possibility of JAK/STAT inhibition as a targeted therapy. IL-2–inducible T-cell kinase is crucial for T-lymphocyte development and in the pathophysiology of T-cell malignancies; it is another promising target being explored in drug development. PI3K pathway inhibitors are being studied, as well as a number of new monoclonal antibodies and antibody-drug conjugates, such as pertuzumab and mogamulizumab, an anti-CCR4 antibody.
An antibody-drug conjugate against CD3 with diphtheria toxin conjugate is in clinical phase. Immune checkpoint inhibitors such as anti–PD-1 antibody are also being developed for the treatment of leukemic variants of CTCL.
Merkel Cell Carcinoma Update
Merkel cell polyomavirus (MCPyV) is a newly discovered human virus that causes MCC. MCPyV may function as an immune target in MCC, said Isaac Brownell, MD, PhD, at the meeting.
The polyomavirus family expresses T (tumor) antigens. Expression of T antigens “is like taking the brakes out of the cell cycle and driving a proliferative state, which is conducive to forming a tumor,” said Brownell, in describing the role of MCPyV in the pathogenesis of MCC.
MCPyV is common; by adulthood, almost everybody has circulating antibodies in the blood, indicating infection by this virus at some time in their lives.
To cause MCC, MCPyV must be integrated into the host genome. In addition, a mutation must occur in the large T antigen, which removes its helicase activity, making virus replication difficult.
MCPyV also interacts with the immune system, most likely at 2 different stages. “It’s possible that as people age, they lose their protective immunity to polyomavirus, and this may allow an expansion of this virus, making it more likely for these 2 integration and mutation events to occur,” said Brownell, head, Cutaneous Development and Carcinogenesis Section, Dermatology Branch, Center for Cancer Research at the National Cancer Institute.
While the immune system may clear the subsequent transformed cells, denying tumor expansion, in a person with a healthy immune system, the tumor will expand in a person with a defective immune system.
At present, no gold standard to detect MCPyV exists, and no CLIA test is certified. Polymerase chain reaction (PCR) is most often used in the research setting, but there’s no gold standard PCR test, he said. Depending on the PCR approach, MCPyV is detected in 50% to 100% of tumors.
A number of antibodies can detect viral proteins, particularly T antigens, but only the CM2B4 is commercially available. “It has a lower sensitivity than PCR; we know that there are virus-positive tumors that don’t stain for CM2B4,” he said.
On serology, people with MCC have a higher level of antibodies against viral peptides circulating in their blood. However, people with MCPyV-negative tumors can have high serology titers, and the reason is not clear.
The clinical significance of MCPyV detection in a Merkel cell tumor is also uncertain. Among a cohort of MCC patients from Finland, those with virus-positive tumors had a better prognosis than those with virus-negative tumors. “It may be that a tumor that expresses a non-self viral protein is a better target for the immune system to hone in on to clear that tumor,” said Brownell.
However, studies examining survival have produced conflicting results, with some finding improved survival in patients with MCPyV-positive tumors, while others have found no difference in outcomes between patients with MCPyV-positive and -negative tumors.
Few studies have examined serological tests to determine prognosis in MCC or risk for the disease. A validated serology test, available as a send-out test through the University of Washington in Seattle, demonstrated that detection of MCPyV small T-antigen antibodies reflects tumor load in some patients, offering a means to detect recurrence after treatment.
Potential for Immunotherapy
MCPyV may be an immune target in MCC, said Brownell. “About half of MCC patients will have circulating T cells that will react to the MCPyV, and about one-third of those patients will have circulating T cells that are reactive to the T-antigen expressed by the virus,” he said. “This could be leveraged to use T cells to treat these patients.”
A phase 1/2 trial of MCPyV-reactive autologous T-cell therapy for metastatic MCC is being conducted at the Fred Hutchinson Cancer Research Center in Seattle, WA. Patients are being treated with adoptive CD8+ MCPyV-reactive T cells after major histocompatibility complex class I up-regulation with radiation therapy or intralesional interferon.
Updated MCC Guideline
Most patients with MCC are diagnosed in an early stage where most advances in treatment have been made in recent years, said Christopher Bichakjian, MD, who provided the most recent update to the National Comprehensive Cancer Network (NCCN) guideline on MCC.
The first addition is a footnote stating that “imaging may be useful to identify and quantify regional and distant metastases.”
Antibodies to MCPyV-specific oncoproteins have been discovered in 40.5% of MCC cases. Among MCC patients with serum antibody, titers fell or remained stable in 226 of 231 samples from patients who remained disease-free, for a specificity of 97.8%. In 14 of 18 patients who progressed within 30 days from blood draw, oncoprotein antibody titer increased at least 20% (sensitivity 77.8%); in 4, increasing titers preceded clinical recognition.
“It is a very interesting development that may provide us with a prognostic tool that may either supplement or replace certain imaging studies that we’re doing now in a routine for patients with MCC,” said Bichakjian, director, Multidisciplinary Merkel Cell Carcinoma Program, University of Michigan, Ann Arbor.
The NCCN advised changes in the treatment of both primary and adjuvant therapy for node-negative patients, which represent most patients with MCC.
A clear conceptual separation in the treatment algorithm was established between the management of the primary site and the regional nodal basin in relation to surgery and radiation therapy.
The second minor change was to encourage observation of the nodal basin in patients with a negative sentinel lymph node biopsy. Sentinel lymph node status is the most prognostic predictor of recurrence-free and overall survival, and the results should be trusted, said Bichakjian. “The point is that if you’re doing a sentinel lymph node biopsy, if your result is negative, you should trust that result,” he said. “If you don’t trust that result, you probably shouldn’t be doing it in the first place.”
The third update was to discourage morbid resection for extensive disease in favor of adjunct radiation therapy. If a clear surgical margin around an infiltrative tumor is difficult to achieve, this would be an indication for adjunct radiation. “We’re not saying not to do surgery,” he said. “These patients should have surgery, if nothing else, to debulk this tumor.”
The fourth update of importance is the recommendation to consider observation of the primary tumor bed in low-risk patients following surgery. He shared data from his institution on a cohort of 113 patients with primary MCC who did not have radiation to the primary tumor. The size of the primary tumor was 1 cm in 57%, 1 to 2 cm in 36%, and 2 cm in 7%. Few patients had nodal disease, and angiolymphatic invasion was absent in three-fourths.
With a mean follow-up of 31 months, recurrence of MCC was 21%, but only 1 patient (0.9%) had a local recurrence. One patient had a concurrent local and in-transit recurrence, and 1 other patient had a concurrent satellite and regional recurrence. “There were 3 people who could have possibly benefited from adjunct radiation therapy to the primary site,” he said.
Seventeen of the 24 (71%) patients who had a recurrence had stage 3 disease at the time of presentation. The remaining 7 had regional or distant recurrence without local recurrence.
“We are not trying to say that primary MCC should not be radiated at the primary site,” said Bichakjian. “But at least that there is a well-defined and probably fairly sizeable group of people who could probably be treated curatively with surgery at the primary site, without the morbidity and cost associated with several weeks of adjunct radiation therapy.”
For patients with clinical M1 disease, the updated NCCN guideline urges enrollment in a clinical trial, if available.
A Principles of Excision page reiterates that surgical margins should be balanced with the morbidity of surgery. “The first goal is to obtain histologically negative margins, when clinically feasible,” he said.
Efforts in Prevention and Early Detection of Skin Cancers Are Bearing Fruit
Prevention and early detection of melanoma, recurrent MCC, and other skin cancers were the focus of a session.
Susan M. Swetter, MD, spoke about the potential for chemoprevention of primary melanoma. Clinically atypical nevi (CAN) may manifest markers of progression or predictive response markers and might therefore be appropriate for evaluation of early-phase candidate chemoprevention agents.
The reported frequency of CAN among patients with a history of melanoma ranges from 34% to 59%. The goal of chemoprevention of melanoma would be to prevent an initial cancer in high-risk individuals, to prevent cancers in those with premalignant conditions, and to prevent secondary primary cancer, said Swetter, codirector, Pigmented Lesion & Melanoma Program, Stanford University Medical Center and Cancer Institute, Stanford, CA.
“Early detection is critical to reducing mortality,” she said. Fifty-eight percent of all melanoma deaths are in white men ?50 years of age. This group is less likely to have a regular healthcare provider, receive routine preventive care, and participate in cancer prevention programs. Further, data from registries show that women have a consistent 30% advantage in overall survival, disease-specific survival, and time to lymph node metastases and distant metastases compared with men. For these reasons, there is a rationale for targeting older men for prevention. In the Cancer Prevention Institute of California/Stanford collaboration, males accounted for 40% of the melanoma cases overall but comprised 64% of melanoma-specific deaths.
Health behaviors and practices play a large role in prevention. Thinner tumors are related to physician detection versus self-detection, higher education, and non-nodular subtypes of melanoma.
Biologic sex differences in melanoma have been proposed, including differences in vitamin D metabolism, immune homeostasis and regulation, methylation, and ultraviolet radiation–induced gene mutations and exposure patterns, “but the bottom line is we really don’t know,” said Swetter.
MCC Serologic Assay
Serology may allow early detection of MCC, when a tumor may be more amenable to immune therapy, said Nghiem in describing a new serologic assay for early detection of recurrent MCC.
Half of MCCs will recur, and most will be fatal, emphasizing the need for early detection of recurrence. “The Merkel polyomavirus [MCPyV] drives most MCCs,” said Nghiem.
Humoral immunity is a powerful biomarker. The T antigen of MCPyV, present in 80% of MCC tumors, is critical for most MCC tumors to grow. Antibodies that recognize this oncoprotein are present in about 50% of newly diagnosed MCCs. These antibodies are present in <1% of controls without MCC, even though about half of all people have the Merkel virus oncoprotein on normal skin at any time.
The level of antibodies to MCPyV decreases rapidly after treatment, and by 1 year after successful treatment are reduced by about 90%. With recurrence, antibody levels rise rapidly among the patients who had antibodies to MCPyV at the time of their first cancer.
Nghiem’s laboratory has developed a clinical MCPyV antibody assay, available since January 2014. “We are detecting our body’s response to a cancer-associated protein; that is, the antibody to it,” he said.
The process has been long and challenging. His team has collected 1342 samples from 104 controls and 519 MCC patients from around the world that had to be correlated with clinical status on the day the blood was drawn. A complex logic was required to determine how to interpret the results. A 75-step assay that takes 1.5 days is demanding, and the proteins used in the preps must be highly reproducible.
“The observed titer vs the predicted titer has a beautiful relationship, and similarly, stability over greater than 1 year,” he said. Of the 104 control subjects, 98% were seronegative for oncoprotein, compared with 47% of 219 MCC patients. Those who are likely to make antibodies have classic CK20+ MCC, are immunocompetent, and are younger (?65 years). The hazard ratio for MCC-specific survival is 0.46 for those who are oncoprotein antibody-positive versus antibody-negative.
“We tend to scan more often in the oncoprotein antibody-negative people and a lot less often in those who are antibody positive,” he said.
Oncoprotein antibodies have been shown to predict MCC recurrence. The test also has the potential to be useful to predict recurrence in the next 6 months: a decreasing titer at the time of a second blood draw was associated with a low chance of recurrence, and an increasing titer was a significant predictor of recurrence.
Skin cancer screening in Germany has proved to be valuable in increasing detection, said Hauschild.
He described a systematic skin cancer screening program in northern Germany called SCREEN (Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany). All residents of Schleswig-Holstein with statutory health insurance were eligible for whole body examination (from July 2003 to June 2004) by a physician who had undergone an 8-hour training course. The screening model used a 2-step program. Subjects first visited a general practitioner; if a suspicious lesion was found, the patient was referred to a dermatologist, who conducted a second whole body examination and a biopsy if necessary, followed by excision of a cancerous lesion. Alternatively, subjects could go directly to a dermatologist, bypassing the general practitioner.
Most insurance companies offered skin cancer screening for volunteers ?20 years of age, and some even earlier, said Hauschild.
During the 1-year pilot trial, 3100 skin cancers were detected. The impact on incidence was clear, with a rising incidence of cancer during screening, and a decreased incidence thereafter. Mortality rates declined over time and were 52% lower over the following 10 years in Schleswig-Holstein, but not in other neighboring regions.
The program shows that early detection is feasible and that the observed reduction in mortality is most likely caused by screening. The current skin cancer incidence in Germany has increased by 30% since 2003.
On November 12, 2014, the Personalized Medicine Coalition (PMC) celebrated its 10th anniversary at the 10th Annual Personalized Medicine Conference at the Harvard Medical School. The occasion gave us a chance to review the progress of personalized medicine and to reflect on the continuing challenges facing the field. Personalized medicine [ Read More ]
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