Immunotherapy for Non-melanoma Skin Cancer.

PURPOSE OF REVIEW: The therapeutic landscape for non-melanoma skin cancer (NMSC) has recently expanded with the development of effective and targeted immunotherapy. Here, we provide an overview of the role of immunotherapy in the management of advanced cutaneous carcinomas. RECENT FINDINGS: Several agents were recently U.S. Food and Drug Administration (FDA)-approved for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma, Merkel cell carcinoma, and basal cell carcinoma. However, recent approvals in tissue-agnostic indications may also benefit other NMSCs including cutaneous adnexal solid tumors with high tumor mutation burdens or microsatellite instability. Furthermore, while FDA-approved indications will likely continue to expand, continued studies are needed to support the role of immunotherapy in the neoadjuvant, adjuvant, and refractory settings. Immunotherapy is emerging as the standard of care for several advanced NMSCs not amenable to surgery and radiation. Ongoing evaluation of the clinical trial landscape is needed to optimize enrollment and ensure continued innovation.

Basal cell carcinoma treated with combined ablative fractional laser and ingenol mebutate - an exploratory study monitored by optical coherence tomography and reflectance confocal microscopy.

BACKGROUND: Basal cell carcinomas (BCCs) have previously been treated off-label with ingenol mebutate (IM). Ablative fractional laser (AFL) may improve efficacy of IM by increasing drug uptake in the tumour. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) detect BCC non-invasively. Our aim was to investigate BCC response and tolerability after combined AFL and IM treatment of low-risk BCCs. METHODS: Twenty patients with histologically verified superficial (n = 7) and nodular (n = 13) BCCs were treated with combined fractional CO2 -laser (10 600 nm) and IM 0.015% or 0.05%, the concentration depending on anatomical location. BCC response was evaluated clinically, by OCT and RCM at day 29 and 90 after first treatment, and histologically at day 90. Treatment was repeated at day 29 if BCC persisted. Local skin reactions (LSRs) were assessed using LSR scale at all visits. RESULTS: At day 29, 18/20 patients received a second treatment due to residual BCC detected clinically, by OCT or RCM. OCT and RCM presented subclinical BCCs in five of 20 cases (25%). At day 90, overall histological cure rate was 70%, corresponding to clinical (65%) and OCT/RCM (60%) cure rates, and agreement between evaluation methods was substantial (kappa ≥ 0.796, P < 0.0001). Clearance rates were similar for sBCCs and nBCCs (P = 0.354) and for lesions treated with IM 0.015% and 0.05% (P = 0.141). LSRs were tolerable, but scarring was observed in the majority of cleared patients. CONCLUSION: Two treatments of combined AFL and IM show potential to treat low-risk BCCs with acceptable tolerability. OCT and RCM show promise to detect subclinical BCCs at short-term follow-up.

Evaluation of AAV-mediated delivery of shRNA to target basal-like breast cancer genetic vulnerabilities.

Adeno-associated viral vectors (AAV) for gene therapy applications are gaining momentum, with more therapies moving into later stages of clinical development and towards market approval, namely for cancer therapy. The development of cytotoxic vectors is often hampered by side effects arising when non-target cells are infected, and their production can be hindered by toxic effects of the transgene on the producing cell lines. In this study, we evaluated the potential of rAAV-mediated delivery of short hairpin RNAs (shRNA) to target basal-like breast cancer genetic vulnerabilities. Our results show that by optimizing the stoichiometry of the plasmids upon transfection and time of harvest, it is possible to increase the viral titers and quality. All rAAV-shRNA vectors obtained efficiently transduced the BLBC cell lines MDA-MB-468 and HCC1954. In MDA-MB-468, transduction with rAAV-shRNA vector targeting PSMA2 was associated with significant decrease in cell viability and apoptosis induction. Importantly, rAAV2-PSMA2 also slowed tumor growth in a BLBC mouse xenograft model, thus potentially representing a therapeutic strategy against this type of cancer.

A qualitative study of the knowledge, behaviour and attitudes of patients with skin cancer regarding sunlight exposure and vitamin D.

BACKGROUND: Solar UVR is a major cause of skin cancer but also an important source of vitamin D (VitD), essential for musculoskeletal health. Conflicting public health messages may confuse patients with skin cancer prone to further skin cancer. OBJECTIVE: To explore the knowledge, behaviour and attitudes of patients with skin cancer to sunlight exposure and VitD sources. METHODS: Patients (n = 10) previously treated for multiple basal cell cancer in a hospital setting participated in focus group sessions with semi-structured discussions to explore: knowledge of VitD, sun-avoidance behaviour and attitude towards sunlight exposure messages. Thematic data analysis was performed using software programme MAXQDA11. RESULTS: Pre-existing knowledge of VitD was low. Most patients practised sun avoidance and were not inclined to increase exposure. Patients did not perceive VitD deficiency as a substantial risk to their own health, or a need to take VitD supplements. They aimed to increase VitD status through dietary intake, but knowledge of food VitD content was lacking. CONCLUSIONS: The patients with skin cancer, appropriate to their heightened skin cancer risk, appeared unlikely to increase their sun exposure to gain VitD. However, education is required regarding the generally low levels of VitD in foodstuffs, and the requirement for supplements/fortified foods if strict sun avoidance is employed.

Skin cancer.

Essential facts Skin cancer can be split into 2 groups: malignant melanoma, which can be fatal; and non-melanoma, such as squamous cell carcinoma and basal cell carcinomas, which are rarely lethal. In 2013 there were 14,509 new cases of malignant melanoma in the UK and, in 2014, 2,459 people died from the disease. Non-melanoma skin cancers are more common; 72,100 new cases were diagnosed in the UK in 2013.

Basal-like breast cancer: update on clinicopathologic, immunohistochemical, and molecular features.

CONTEXT: Basal-like breast carcinoma (BLBC) is a distinct molecular subtype of breast carcinoma identified through gene expression profiling studies. OBJECTIVE: To provide the clinical background, the histologic profile, and the immunohistochemical profile of these tumors and discuss the current knowledge of their molecular signature and their implications on targeted molecular therapy. DATA SOURCES: Data were obtained from review of the pertinent peer-reviewed literature. CONCLUSIONS: Basal-like breast carcinomas are aggressive tumors with poor prognosis. Lack of targeted therapy makes their treatment a challenging task. Traditional chemotherapy is still associated with a high risk of relapse and death in a high percentage of patients. Platinum-based chemotherapy has been considered as a candidate for the treatment of BLBCs owing to their BRCA1 phenotype. Approximately 22% of patients treated with single-agent cisplatin show pathologic complete response, which is a comparable rate to that seen with nonplatinum agents. Antiangiogenic agents have been promising, but their currently demonstrated limited response is considered disappointing. Additionally, epidermal growth factor receptor was not shown to be a helpful target for BLBC. A recent study has shown that BLBC appears to be especially sensitive to MEK inhibitors, making it a promising therapeutic possibility. The list of new targets is still evolving and the "magic" therapeutic target is yet to be discovered.

Systemic therapy for inoperable and metastatic basal cell cancer.

Cutaneous basal cell carcinoma (BCC) is the most common human malignancy. The majority of cases are cured with local therapies and advanced disease is quite rare. However, locally advanced (inoperable) and metastatic basal cell carcinoma may occur more often than previously thought. Surgery, and other local therapies, is the primary treatment for BCC. However, some resections can be extensive and carry significant morbidity or disfigurement. The prognosis for locally advanced and metastatic BCC is quite poor, and cytotoxic chemotherapies offer limited benefit. Aberrations in the sonic hedgehog (HH) signaling pathway are common in BCC. Novel molecular therapies targeted against this pathway, such as vismodegib (GDC-0449), have shown dramatic activity in advanced basal cell carcinoma. The role of these in nevoid basal cell carcinoma syndrome (Gorlin) syndrome is still under investigation. However, systemic therapies are not curative and require long-term treatment and should not be used in place of curative procedures. Evaluation by experienced physicians and/or by a multidisciplinary tumor board for possible curative/definitive surgery with or without radiation is recommended before initiation of systemic therapy. Clinical trial enrollment also is recommended. Comorbid conditions as well as social circumstances may be factors when deciding on an optimal therapy, in particular with oral agents. Patients treated with HH pathway inhibitors require regular physician monitoring to assess for side effects, benefit, and compliance. Patients of child-bearing potential must be strongly counseled regarding the risk of birth defects and need for birth control. Primary and secondary resistance to HH pathway inhibitors is only beginning to be described.

Metastatic breast cancer in a Nigerian tertiary hospital.

BACKGROUND: Late presentation of breast carcinoma is common in resource-limited countries with attendant poor outcome. OBJECTIVE: To describe the pattern of clinical presentation and challenges of treating patients presenting with metastatic breast carcinoma in a Nigerian hospital. METHOD: Clinical records of all patients who presented with metastatic breast carcinoma between January 1991 and December 2005 at the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria were reviewed. RESULTS: More than half of all histologically confirmed breast cancer patients seen within the study period presented with metastatic disease. Their ages ranged between 20-81 years with a mean age of 45.9 years. Only 3% (6 of 202) were males. Two-thirds had more than one secondary site on initial evaluation and the commonest sites were liver (63%), lung parenchyma (51%), pleura (26%) and contralateral breast in 25%. On immunohistochemistry, basal like tumours were found in 46.1%. Mastectomy was done in 37 patients with fungating breast masses while only one third of those referred to a nearby center for radiotherapy had it done. One year survival rate was 27%. CONCLUSION: Metastatic disease is common in Nigeria and treatment is limited due to resource limitations. Improved awareness of the disease is advocated to reduce late presentation.

EGFR/HER2 in breast cancer: a biological approach for molecular diagnosis and therapy.

Novel cancer therapies have focused on specific molecular markers present in malignant tumors. The rationale of targeted therapy relies on the knowledge of molecular mechanisms involved in carcinogenesis and their influence in clinical outcome allied to a more specific and less toxic treatment. Activation of EGF receptor and HER2 is an important factor for initiation and progression of malignancies, including breast cancer where the status of HER2 is an essential step in the diagnostic workup; EGFR overexpression has been associated to the so-called basal-like breast carcinomas, which opens a new avenue for diagnosis and therapeutic approach in these tumors. This review will focus on mechanisms of HER2 and EGF receptor upregulation, the targeted therapies that are currently in use for these receptors, possible combined therapies, as well as the approach for molecular diagnosis from the pathologist's point of view.

Basal-like breast cancer: a critical review.

Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic, and therapeutic implications. The basal-like group of tumors is characterized by an expression signature similar to that of the basal/myoepithelial cells of the breast and is reported to have transcriptomic characteristics similar to those of tumors arising in BRCA1 germline mutation carriers. They are associated with aggressive behavior and poor prognosis, and typically do not express hormone receptors or HER-2 ("triple-negative" phenotype). Therefore, patients with basal-like cancers are unlikely to benefit from currently available targeted systemic therapy. Although basal-like tumors are characterized by distinctive morphologic, genetic, immunophenotypic, and clinical features, neither an accepted consensus on routine clinical identification and definition of this aggressive subtype of breast cancer nor a way of systematically classifying this complex group of tumors has been described. Different definitions are, therefore, likely to produce variable and contradictory results that may hamper consistent identification and development of treatment strategies for these tumors. In this review, we discuss definition, heterogeneity, morphologic spectrum, relation to BRCA1, and clinical significance of this important class of breast cancer.

JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer.

Expression of the JAG1 Notch ligand has previously been shown to correlate with poor overall survival in women with advanced breast cancer. We undertook to test whether expression of JAG1 is associated with reduced disease free survival (DFS) in 887 samples from a prospectively accrued LNN cohort with a median follow-up greater than 8 years. Moderate to high JAG1 mRNA expression was associated with reduced DFS in univariate analysis (hazard ratio of 1.58; 95% confidence interval, 1.03-2.40; P = 0.034) and correlated with large tumor size, ER and PgR negativity, high tumor grade, and p53 antibody reactivity. Although elevated risk of reduced DFS in patients with high JAG1 mRNA did not persist with adjustment for other prognostic factors, it did in combination with HER2. JAG1 mRNA was positively associated with expression of basal breast cancer markers, however, in contrast to the finding that basal gene expression is most strongly associated with reduced DFS in the first 36 months of follow-up, JAG1 mRNA expression was associated with reduced DFS through the full follow-up period. Also, tumors expressing high levels of both mRNA and protein showed reduced DFS as compared to all other groups in univariate analysis (hazard ratio of 1.73; 95% confidence interval, 1.09-2.74; P = 0.020). Thus, JAG1 expression is associated with poor DFS in LNN breast cancer. As JAG1 is a target of several oncogenic signaling pathways, and is a ligand for Notch, these data provide novel insights into signaling that may contribute to progression of early stage breast cancer.

Deconstructing the molecular portrait of basal-like breast cancer.

Gene-expression profiling has revealed several molecular subtypes of breast cancer, which differ in their pathobiology and clinical outcomes. Basal-like tumors are a newly recognized subtype of breast cancer, which express genes that are characteristic of basal epithelial cells, such as the basal cytokeratins, and are associated with poor relapse-free and overall survival. However, the genetic and epigenetic alterations that are responsible for the biologically aggressive phenotype of these estrogen receptor-negative and HER2/ErbB2-negative tumors are not well understood, thereby hindering efforts to develop targeted therapies. Here, we focus on new insights into the molecular pathogenesis of basal-like breast cancer and explore how these discoveries might impact the treatment of these poor-prognosis tumors.

Basaloid squamous cell carcinoma of the uterine cervix with an uncommon metastasis to the left iliac region--case report.

We describe a rare and interesting case of a basaloid squamous cell carcinoma (BSC) of the uterine cervix with metastasis in the left iliac region diagnosed by fine needle aspiration (FNA). A 54-year-old woman underwent FNA because of a mass in the left iliac region. The material was processed by conventional liquid based cytology (ThinPrep), and by the cell-block technique and diagnosis was based on the cytomorphologic and immunochemical characteristics as well as the patient's history. The cytologic diagnosis concerned a poorly differentiated squamous cell carcinoma. After a laborious search, we found out that the patient had undergone a total hysterectomy almost 15 years before. The histological diagnosis then was an "infiltrative squamous cell carcinoma of basaloid type" of the uterine cervix. Our case is of particular interest because it is a rare type of neoplasm with an unusual site of metastasis after a long disease-free period.

Identification of skin cancers 1: benign and premalignant lesions.

Skin cancers are the most commonly diagnosed cancer in the UK, and their incidence is growing. They can present in all age groups, and are particularly common in older people, but the incidence among younger people is increasing. However, the majority of skin lesions are not malignant. In this, the first of two articles, the author discusses the range of common benign growths that can be mistaken for cancers, as well as the precancerous lesions that can become a cause for concern if untreated. The second article will examine the common malignant lesions.

Multiple familial trichoepithelioma: a rare cutaneous tumour.

Multiple familial trichoepithelioma (MFT) is a rare autosomal dominant skin disease that present as many small tumours predominantly on the face. We report a case of multiple familial trichoepithelioma occurring in three members of a family. They were diagnosed simultaneously. Only one was treated with medium depth chemical peeling with partial response.

Skeletal metastasis in tricholemmal carcinoma.

Tricholemmal carcinoma is an extremely rare cutaneous adnexal tumor, not exceeding 1-2 cm in diameter in some reported cases. The few reports describe only a greater histologic malignancy. Some cases of recurrences have been reported, and metastasis of the soft tissue was described once by Amaral et al in 1984. In the current patient with tricholemmal carcinoma of the right distal thigh, the primary tumor was unusually large. The first detected metastasis was localized in the right inguinal lymph nodes. Five years after diagnosis of tricholemmal carcinoma a metastasis of the left tibia and fibula were diagnosed. To our knowledge, an osseous metastasis in tricholemmal carcinoma has not been described. It is possible that a relationship between the extraordinary size and the osseous metastasis exists in the current patient.