Breast Cancer Skin Metastases Research Articles

Electrochemotherapy of skin metastases from breast cancer: a systematic review.

Skin metastases occur in 5-30% of breast cancer (BC) patients. Standard treatments include systemic therapies (chemotherapy, endocrine therapy, and immunotherapy) and local treatments (surgery and radiotherapy). Electrochemotherapy (ECT) could be another option in this setting based on preclinical and clinical studies. Aim of this review was to analyze the available evidence on ECT in skin metastases from BC. Studies reporting on ECT in skin metastases from BC were included in this review. Studies not reporting toxicity or tumor response or not reporting results separately from other primary cancers were excluded. The search was based on Medline, Scopus, and The Cochrane Library databases. Eleven studies including 464 patients were analyzed. ECT was performed using intravenous/intratumoral bleomycin (10 studies) or intratumoral cisplatin (one study). Complete and overall pooled response rates were 46.2% (95%CI 33.2-59.4 and 74.6% (95%CI 60.6-86.4) in studies reporting results on a per patient basis and 61.9% (95%CI 53.8-69.6) and 86.9% (95%CI 80.0-92.6) in studies reporting results on a per lesion basis, respectively. Worse response rates in larger lesions were observed in three studies. The incidence of toxicity was heterogeneous but adverse events were mild and manageable in all studies. One- and 3-year local progression-free survival was 86.2% and 81.0% in two studies, respectively. ECT is tolerable and effective in terms of response in BC skin metastases especially in less advanced lesions. Further studies are justified to compare ECT with other treatments in this setting.

Transcriptomic profiles conducive to immune-mediated tumor rejection in human breast cancer skin metastases treated with Imiquimod

Imiquimod is a topical toll-like-receptor-7 agonist currently used for treating basal cell carcinoma. Recently, imiquimod has demonstrated tumor regression in melanoma and breast cancer skin metastases. However, the molecular perturbations induced by imiquimod in breast cancer metastases have not been previously characterized. Here, we describe transcriptomic profiles associated with responsiveness to imiquimod in breast cancer skin metastases. Baseline and post-treatment tumor samples from patients treated with imiquimod in a clinical trial were profiled using Nanostring technology. Through an integrative analytic pipeline, we showed that tumors from patients who achieved a durable clinical response displayed a permissive microenvironment, substantiated by the upregulation of transcripts encoding for molecules involved in leukocyte adhesion and migration, cytotoxic functions, and antigen presentation. In responding patients, Imiquimod triggered a strong T-helper-1 (Th-1)/cytotoxic immune response, characterized by the coordinated upregulation of Th-1 chemokines, migration of Th-1 and cytotoxic T cells into the tumor, and activation of immune-effector functions, ultimately mediating tumor destruction. In conclusion, we have shown that topical imiquimod can induce a robust immune response in breast cancer metastases, and this response is more likely to occur in tumors with a pre-activated microenvironment. In this setting, imiquimod could be utilized in combination with other targeted immunotherapies to increase therapeutic efficacy.

Eccrine poroma: The prominent mimicker

Background: Eccrine poroma (EP) is an adnexal benign tumor arising from the eccrine duct epithelium. The appearance of EP can mimic benign and malignant skin tumors, thus often making the diagnosis delayed or inaccurate. Case Illustration: We report two cases of EP, with clinical and dermoscopic features mimicking Bowen’s disease, verruca vulgaris, pyogenic granuloma, skin metastases of breast cancer, and amelanotic melanoma. Both patients were surgically excised and biopsied. Histopathology examination of both cases revealed eccrine poroma. Discussion: Both cases showed similarity with the theories, that EP is most found in middle age population and its predilection on extremities. The dermoscopy appearance of the first patient showed two major components, multiple red dots and lacunae mimicking glomerular vessels, and multiple whitish halos-likekeratosis. Red dots with whitish halos can be seen in dermoscopy of verruca vulgaris, while glomerular vessels and keratosis is usually found in Bowen’s disease. The dermoscopy examination of our second patient only showed some loop hemorrhagic and thrombosed vessels, which are quite inconclusive. Diagnoses were made with histopathology examination which revealed similar pattern of eccrine poroma in both cases. Conclusion: EP is a prominent mimicker, often misdiagnosed because it is uncommon in clinical practice, has variable clinical presentations and dermoscopic appearances. Hence, recognizing and diagnosing this disease becomes a challenge for dermatologist. Keywords: adnexal tumor, dermoscopy, eccrine poroma

Electrochemotherapy in the treatment of cutaneous metastases from breast cancer: a multicenter cohort analysis

Background: The management of breast cancer (BC) skin metastases represents a therapeutic challenge. Electrochemotherapy (ECT) combines the administration of bleomycin with temporary permeabilization induced by locally administered electric pulses. Preliminary experience with ECT in BC patients is encouraging. Methods: A total of 125 patients with BC skin metastases who underwent ECT between 2010 and 2013 were enrolled onto a multicenter retrospective cohort study of the GISEL group (Gruppo Italiano Senologia ed Elettrochemioterapia). The treatment was administered following the European Standard Operative Procedures of Electrochemotherapy. Tumor response was clinically assessed adapting the Response Evaluation Criteria in Solid Tumors, and toxicity was evaluated according to Common Terminology Criteria for Adverse Events 4.0. Cox regression analysis was used to identify predictive factors. Results: Response was evaluable in 113 patients for 214 tumors (median 1 per patient, range 1–3). The overall response rate after 2 months was 90.2%, while the complete response (CR) rate was 58.4%. In multivariate analysis, small tumor size (P < 0.001), absence of visceral metastases (P = 0.001), estrogen receptor positivity (P = 0.016), and low Ki-67 index (P = 0.024) were significantly associated with CR. In the first 48 h, 10.4% of patients reported severe skin pain. Dermatologic toxicity included grade 3 skin ulceration (8.0%) and grade 2 skin hyperpigmentation (8.8%). Tumor 1-year local progression-free survival was 86.2% (95% confidence interval 79.3–93.8) and 96.4% (95% confidence interval 91.6–100) in the subgroup of those with CR. Conclusions: In this study, small tumor size, absence of visceral metastases, estrogen receptor positivity, and low Ki-67 index were predictors of CR after ECT. Patients who experienced CR had durable local control. ECT represents a valuable skin-directed therapy for selected patients with BC. A new prospective protocol has been recently approved by the coordinator centre of Padova for an observational multicentre study on BC patients treated with ECT. GISEL group is open to new centres interested in giving their contribution to the study.

Identification of differentially expressed genes associated with clinical response after treatment of breast cancer skin metastases with imiquimod.

e12541 Background: Imiquimod, a Toll-like receptor 7 agonist, activates innate immunity and has a response rate of 20% in breast cancer skin metastases. Tumor regression is associated with increased tumor infiltrating lymphocytes and increased Th1 cytokines in tumor supernatant, however gene expression changes are unknown. This is the first report of gene expression changes induced by imiquimod treatment in breast cancer skin metastases. Methods: FFPE-extracted mRNA from 8 patients pre and post 8 weeks of imiquimod treatment was analyzed using Nanostring PanCancer Immune Profiling Panel. Gene expression and pathway analysis was conducted with nSolver 3.0 with clinical response as outcome, controlling for HER2 ER/PR status, with 5% significance level used. Results: In all patients, imiquimod was associated with upregulation of genes in innate immunity such as TLR7, IL-1, T-cell, B-cell, and NK related genes. Three patients had a clinical response after imiquimod. Forty-two differentially expressed genes were identified in responders vs. non-responders after imiquimod. Reponders had up-regulation of T cell (CD2, SPN), NK cell (KLRC2), B cell (CD48), lymphocyte (LY96), and IL-2 (IL2RG) related genes. The top upregulated pathways were cytotoxicity, NK cell function, and antigen processing. Pre-treatment, the responders had upregulation of TNF and IL-17 related genes (TNFRSF10B, IL17RA) compared to non-responders. Comparing pre-treatment to post-treatment, Imiquimod was associated with mRNA expression changes in 72 genes in responders vs non responders. The top upregulated genes involved activation of lymphocytes (SH2D1A), NK cells (KLRC2), DCs (CLEC4C), several chemokines, IL7R and immune regulators PLD1 and IRF5. Conclusions: Clinical response to Imiquimod treatment of breast cancer skin metastases is associated with upregulation of genes in innate immunity suggestive of an anti-tumor immune response. Inhibition of negative feedback by addition of PLD1 inhibitors may enhance treatment response. Understanding the genetic signature of imiquimod can enhance prediction of response and inform possible combination therapies in the future.

276P - Electrochemotherapy for breast cancer - results from the INSPECT database

Cutaneous recurrence from breast cancer can pose a clinical challenge. It may be the only disease site, or be part of disseminated disease, and often profoundly impacts quality of life. Electrochemotherapy is a palliative treatment for cutaneous metastases. Using electric pulses to locally permeabilize tumor cells, bleomycin cytotoxicity is significantly increased. Collaborating in the International Network for sharing Practice on ElectroChemoTherapy (INSPECT), we consecutively and prospectively accrued data on patients treated with electrochemotherapy for skin metastases of breast cancer. Patients with cutaneous metastases were treated with electrochemotherapy at 10 European centers. Treatment data and results were entered into the INSPECT database. Patients were treated with either local injection (1000 IU/ml intratumoral injection) or systemic infusion (15.000 IU/m2) of bleomycin, and under either local or general anesthesia, depending on tumor size. Pulse sequences (8 pulses of 0.1 ms) were sequentially applied to the tumor area, using an electroporation system with needle or plate electrodes (IGEA, Italy). 104 patients were included. Median age was 65 years. Patients had previous received chemotherapy (87%), radiotherapy (83%), endocrine therapy (46%) and HER2 targeted therapy (20%). Primary location was the chest (87%), median diameter of the cutaneous metastases being 26 mm (range 1 mm to 550 mm). 75 patients were available for response evaluation after 2 months. Complete response was observed in 38 (51%) patients, partial response in 13 (17%), stable disease in 14 (19%), and progressive disease in 5 (9%), 3 patients were not evaluable. Common side effects were ulceration, long lasting hyperpigmentation, and slight increase in pain. No serious adverse events were observed. Electrochemotherapy showed high response rates, particularly in smaller metastases. Electrochemotherapy has high response rates seen after a single treatment, with few side effects and can be used as an adjunct to systemic therapies as well as a sole treatment. We therefore highly recommend to consider electrochemotherapy for patients with cutaneous metastases, where radiotherapy and surgery is not an option.

Electrochemotherapy in the Treatment of Cutaneous Metastases from Breast Cancer: A Multicenter Cohort Analysis.

BackgroundThe management of breast cancer (BC) skin metastases represents a therapeutic challenge. Electrochemotherapy (ECT) combines the administration of bleomycin with temporary permeabilization induced by locally administered electric pulses. Preliminary experience with ECT in BC patients is encouraging.MethodsA total of 125 patients with BC skin metastases who underwent ECT between 2010 and 2013 were enrolled onto a multicenter retrospective cohort study. The treatment was administered following the European Standard Operative Procedures of Electrochemotherapy. Tumor response was clinically assessed adapting the Response Evaluation Criteria in Solid Tumors, and toxicity was evaluated according to Common Terminology Criteria for Adverse Events 4.0. Cox regression analysis was used to identify predictive factors.ResultsResponse was evaluable in 113 patients for 214 tumors (median 1 per patient, range 1–3). The overall response rate after 2 months was 90.2 %, while the complete response (CR) rate was 58.4 %. In multivariate analysis, small tumor size (P < 0.001), absence of visceral metastases (P = 0.001), estrogen receptor positivity (P = 0.016), and low Ki-67 index (P = 0.024) were significantly associated with CR. In the first 48 h, 10.4 % of patients reported severe skin pain. Dermatologic toxicity included grade 3 skin ulceration (8.0 %) and grade 2 skin hyperpigmentation (8.8 %). Tumor 1-year local progression-free survival was 86.2 % (95 % confidence interval 79.3–93.8) and 96.4 % (95 % confidence interval 91.6–100) in the subgroup of those with CR.ConclusionsIn this study, small tumor size, absence of visceral metastases, estrogen receptor positivity, and low Ki-67 index were predictors of CR after ECT. Patients who experienced CR had durable local control. ECT represents a valuable skin-directed therapy for selected patients with BC.

Anticancer Therapy for Breast Cancer Patients with Skin Metastases Refractory to Conventional Treatments

Skin metastases of breast cancer are usually late events in the course of tumor progression and signify a poor prognosis. They may remain as a therapeutic challenge especially after failure of standard treatments. Topical interventions, together with or without radiotherapy, may only palliate the symptoms temporarily. However, there may be alternative treatment modalities for unresectable breast cancer skin metastases resistant to chemotherapy and radiotherapy. There are various genetic alterations in tumors and therapeutic potential of expression patterns for factors like epidermal growth factor receptor may have important clinical implications in case of disease refractory to the conventional treatments. Here, we clarified the therapeutic options and genetic alterations in skin metastatic breast cancer patients refractory to standard chemotherapeutics.

Topical TLR7 Agonist Imiquimod Can Induce Immune-Mediated Rejection of Skin Metastases in Patients with Breast Cancer

Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases. A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives. Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%-56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines. Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses.

Evaluation of toll-like receptor (TLR)-7 agonist imiquimod applied topically to breast cancer chest wall recurrences or skin metastases.

TPS138 Background: Purpose: To assess the clinical and biological activity of imiquimod applied topically to breast cancer metastatic to skin. Breast cancer is the most frequent malignancy and the most common tumor, excluding melanoma to metastasize to the skin in women. Chestwall recurrence is debilitating for patients, substantially affecting quality of life (QOL). Current treatment modalities for nonresectable lesions are rarely curative, indicating the need for more effective and less toxic therapies. Imiquimod (IMQ), a synthetic TLR7 agonist has immunomodulatory activity with profound effects on the tumor environment, leading to clearance of primary skin malignancies. We have shown that IMQ recruits and activates dendritic cells (DC) and primes immune responses to coadministered tumor antigens in cancer patients. We have also demonstrated IMQ's antitumor efficacy in BALB/c mouse–derived TSA mammary adenocarcinoma, a poorly immunogenic tumor that ulcerates through the skin, closely mimicking the clinical scenario of patients with chestwall recurrence. Methods: Eligibility includes patients with biopsy-confirmed breast cancer, measurable skin metastases, ECOG PS 0-2 and adequate organ/marrow function. IMQ 5% cream is applied topically to skin metastases overnight for 5 days/week for 8 weeks followed by a 4-week rest period. Additional cycles are permitted. This phase II study uses a Simon optimal two-stage design: 10 patients in stage I (currently 3 enrolled), if response is observed, an additional 19 patients will enroll in stage II. Primary endpoint is 12 week antitumor response, assessed by clinical exam and computer-aided surface area calculation of skin metastases. Furthermore, effects of IMQ treatment on symptoms and health-related QOL will be determined. Tumor biopsies will be studied for immune signatures. Breast cancer skin metastases are infiltrated by inflammatory cells, including DC with markers of activation as well as tolerogenic function (e.g., IDO), and T cells with markers of effector (e.g., granzyme) as well as regulatory functions (e.g., FoxP3). The effect of IMQ treatment on the balance between these subsets will be determined. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Graceway Pharmaceuticals

Miltefosine decreases the cytotoxic effect of Epirubicine and Cyclophosphamide on mouse spermatogenic, thymic and bone marrow cells

A new class of potent anticancer drugs, alkylphosphocholines has been recognized lately. Miltefosine (Hexadecylphosphochlorine, HPC) has been found to express select antineoplastic effect on human breast cancer skin metastases with simultaneous preservation of bone marrow proliferative activity and low clastogenicity. In the current study, we present data about the specific effect of two widely used cytostatics Cyclophosphamide (CP) and Epirubicine (ERb) applied separately or in combination with Miltefosine. C57BL6 mice were treated per os or intraperitonieally in doses corresponding to that in clinical use. Morphological, autoradiographic, ultrastructural and cytogenetic studies on spermatogenic, thymic and bone marrow cells were performed. It is found that compared with separate application, combinations of ERb or CP with Miltefosine slightly decreases spermatogonial proliferation and exerts milder effect on the structure of germinal and thymic cells. In addition, a lot of plasmocytes showed signs of active protein (antibody) synthesis. A significant reduction of aberrant chromosomes (clastogenicity) without changes in proliferative activity of bone marrow cells were recorded. In conclusion, the combine application of Miltefosine with ERb and CP decreased the destructive cytotoxic effects of ERb and CP on mouse spermatogenic and hematopoietic cells.

Treatment of skin metastases of breast cancer.

Although skin metastases of breast cancer are visible, palpable and therefore a bothersome burden to the patient in the psychological and more often in the physical sense by pain and need of care, bandages, foul smell, etc., the paucity of data about incidence and treatment surprises the interested oncologist. Results of treatment are dicult to ®nd, and data on incidence are not easily found in the medical literature. Textbooks on cancer treatment neglect the subject, and literature data found in journals are only sparse.

Human urinary bladder carcinoma cell lines respond to treatment with alkylphosphocholines

Alkylphosphocholines (APC) constitute a new group of antineoplastic agents without haematological toxicity. Their first clinically available derivative hexadecylphosphocholine (miltefosine) is locally used to control skin metastases of breast cancer. Since intravesical chemotherapy represents a form of topical treatment we investigated whether a new APC with a long alkyl chain would be active against 5637 and EJ bladder cancer cell lines. Their antineoplastic activity was inversely related to the alkyl chain length of the respective APC. Erucylphosphocholine and its congener with modified phosphocholine head erucylphospho- N, N, N-trimethylpropanolamine were the most effective derivatives. APC with alkyl chains over 16 carbons in length induced programmed cell death in both cell lines, as determined by oligonucleosomal DNA fragmentation and morphology. The distinct antineoplastic effects lead us to predict that urinary bladder instillation of APC will be of therapeutic benefit for patients with urinary bladder neoplasia.

Möglichkeiten der Iaserinduzierten Fluoreszenzdiagnostik (LIFD) und Photodynamischen Therapie (PDT) bei Hautmetastasen des Mammakarzinoms sowie bei extramammärem M. Paget im Perinealbereich

Die Photodynamische Lasertherapie (PDT) von Karzinomen stellt ein neues Konzept in der Behandlung oberflächlicher Tumoren dar. Sie besteht aus der intravenösen Applikation eines tumorlokalisierenden Photosensibilisators und der nachfolgenden Aktivierung der Substanz durch Licht einer definierten Wellenlänge. Im Gegensatz zur konventionellen Laserbehandlung beruht die destruktive Wirkung der Photodynamischen Therapie nicht auf thermischen, sondern auf photo-chemotoxischen Effekten im Tumor. In der UKF Heidelberg gehört die Photodynamische Therapie bei rezidivierenden Hautmetastasen des Mammakarzinoms zu den palliativen Behandlungsverfahren nach Ausschöpfung konventioneller Therapiemöglichkeiten (Exzision, Laserdestruktion mit thermischem Laser, Radiatio, Chemotherapie). Bei der histologischen Aufarbeitung von Hautprobeexzisionen der bestrahlten Areale fand sich eine gute Ansprechrate der Tumorzellen von 70-100%. Histologische Kontrollen im Langzeit-follow-up stehen noch aus. Für weitere Anwendungsgebiete (z. B. extramammärer M. Paget) werden Behandlungsprotokolle erarbeitet.

First experiences with superfractionated skin irradiations using large afterloading molds

Purpose : Radiotherapy of cutaneous metastases of breast cancer requires large radiation fields and high doses. This report examines the effectiveness and sequelae of superfractioned irradiation of cutaneous metastases of breast cancer with afterloading molds on preirradiated and nonirradiated skin. Methods and Materials : A flexible reusable skin mold was developed for use with a pulsed (PDR) afterloader. An array of 18 parallel catheters was sewn between two foam rubber slabs 5 mm in thickness to provide a defined constant distance to the skin. By selection of appropriate dwell positions, arbitrarily shaped skin areas can be irradiated up to a maximal field size of 17 × 23.5 cm 2. Irradiations are performed with a nominal 37 GBq 192Ir stepping source in pulses of 1 Gy/h at the skin surface. The dose distribution in geometrically optimized. The 80 and 50% dose levels lie 5 and 27 below the skin surface. Sixteen patients suffering from metastases at the thoracic wall were treated with fields (78–798 cm 2) and total doses of 40–50 Gy applying two PDR split courses with a pause of 4–6 weeks. Eleven of the fields had been previously irradiated with external beam therapy to doses of 50–60 Gy at 7–22 months in advance. Results For preirradiated fields ( n = 10) the results were as follows: follow-up 4.5–28.5 months (median 17); local control (LC): 8 of 10; acute skin reaction: Grade 2 (moist desquamation) 2 of 10; intermediate/late skin reactions after minimum follow-up of 3 months: Grade 1 (atrophy/pigmentation): 2 of 10, Grade 2–3a (minimal/marked teleangiectasia): 7 of 10, Grade 4 (ulcer): 1 of 10; recurrencies: 2 of 10. For newly irradiated fields ( n = 7) results were: follow-up: 2–20 months (median 5); LC: 6 of 7; acute reactions: Grade 1:4 of 7, Grade 2:3 of 7; intermediate/late skin reactions after minimum follow-up of 3 months ( n = 5): Grade 2–3a: 2 of 5; recurrencies: 0 of 7. Local control could be achieved in 83% of the mold fields. Geometric optimization was mandatory to achieve a homogeneous dose distribution on the skin. Conclusion : Superfractionated brachytherapy with skin molds is an effective alternative for the treatment of skin metastases of breast cancer even if the skin is preirradiated. This method is economically advantageous compared to external beam therapy, which would require several weeks. At the curved chest wall, optimized molds can provide better dose homogeneity than abutted electron fields. Skin reactions are comparable to the sequelae of orthovolt irradiation. In preirradiated areas, PDR doses should be restricted to 40–45 Gy. PDR doses of 50 Gy seem to be the limit for tolerance even in previously unirradiated fields.