Opinion statement
Melanoma has several clinically and pathologically distinguishable subtypes, which also differ genetically. Mutation patterns vary among different melanoma subtypes, and efficacy of ...immune-checkpoint inhibitors differs depending on the subtype of melanoma. In spite of the recent revolution of systemic therapies for advanced melanoma, access to innovative agents is still restricted in many countries. This review article aimed to describe the epidemiology and current status of systemic therapies for melanoma in Japan, where melanoma is rare, but access to innovative agents is available. Acral and mucosal melanomas, which are common in Asian populations, predominantly occur in sun-protected areas and share several biological features. Both the melanomas harbor KIT mutation in approximately 15% of the cases; BRAF or NRAS mutation is found in approximately 10–15% of acral melanoma, but these mutations are less frequent in mucosal melanoma. Combined use of BRAF and MEK inhibitors is one of the standards of care for patients with advanced BRAF-mutant melanoma. In patients with melanoma harboring KIT mutation in exon 11 or 13, KIT inhibitors can be a treatment option; however, none of them have been approved in Japan. Immune-checkpoint inhibitors are expected to be less effective against acral and mucosal melanomas because their somatic mutation burden is lower than those in non-acral cutaneous melanomas. A recently completed phase II trial of nivolumab and ipilimumab combination therapy in 30 Japanese patients with melanoma, including seven with acral and 12 with mucosal melanoma, demonstrated an objective response rate of 43%. Regarding oncolytic viruses, canerpaturev (C-REV, also known as HF10) and talimogene laherparepvec (T-VEC) are currently under review in early phase trials. In the adjuvant setting, dabrafenib plus trametinb combination, nivolumab monotherapy, and pembrolizumab monotherapy were approved in July, August, and December 2018 in Japan, respectively. However, most of the adjuvant phase III trials excluded patients with mucosal melanoma. A phase III trial of adjuvant therapy with locoregional interferon (IFN)-β versus surgery alone is ongoing in Japan (JCOG1309, J-FERON), in which IFN-β is injected directly into the site of the primary tumor postoperatively, so that it would be drained through the untreated lymphatic route to the regional node basin. After the recent approval of these new agents, the JCOG1309 trial will be revised to focus on patients with stage II disease. In conclusion, acral and mucosal melanomas have been treated based on the available medical evidence for the treatment of non-acral cutaneous melanomas. Considering the differences in genetic backgrounds and therapeutic efficacy of immunotherapy, specialized therapeutic strategies for these subtypes of melanoma should be established in the future.
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently ...required. Here, we show that the frequency of PD-1
CD8
T cells relative to that of PD-1
regulatory T (T
) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8
T cells and T
cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1
CD8
T cells and enhanced PD-1
T
cell-mediated immunosuppression. A profound reactivation of effector PD-1
CD8
T cells rather than PD-1
T
cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Poroma is a benign skin tumor exhibiting terminal sweat gland duct differentiation. The present study aimed to explore the potential role of gene fusions in the tumorigenesis of poromas. RNA ...sequencing and reverse transcription PCR identified highly recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poromas (92/104 lesions, 88.5%) and their rare malignant counterpart, porocarcinomas (7/11 lesions, 63.6%). A WWTR1-NUTM1 fusion was identified in a single lesion of poroma. Fluorescent in-situ hybridization confirmed genomic rearrangements involving these genetic loci. Immunohistochemical staining could readily identify the YAP1 fusion products as nuclear expression of the N-terminal portion of YAP1 with a lack of the C-terminal portion. YAP1 and WWTR1, also known as YAP and TAZ, respectively, encode paralogous transcriptional activators of TEAD, which are negatively regulated by the Hippo signaling pathway. The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic roles. Our results demonstrate the frequent presence of transforming YAP1 fusions in poromas and porocarcinomas and suggest YAP1/TEAD-dependent transcription as a candidate therapeutic target against porocarcinoma.
Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical ...course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum‐free T4 together with elevated thyroid‐stimulating hormone (TSH) >10 μIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty‐three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval CI, 3.53‐23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66‐32.7) and 26.5 (95% CI, 8.18‐85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre‐existing TgAb and elevated TSH at baseline are at high risk of TD.
Thyroid dysfunction induced by immune checkpoint inhibitors is not sufficiently understood. This retrospective observational study revealed that pre‐existing antithyroglobulin Abs and elevated thyroid‐stimulating hormone before nivolumab treatment are risk factors for the development of thyroid dysfunction induced by nivolumab.
Recent studies have demonstrated the usefulness of convolutional neural networks (CNNs) to classify images of melanoma, with accuracies comparable to those achieved by dermatologists. However, the ...performance of a CNN trained with only clinical images of a pigmented skin lesion in a clinical image classification task, in competition with dermatologists, has not been reported to date. In this study, we extracted 5846 clinical images of pigmented skin lesions from 3551 patients. Pigmented skin lesions included malignant tumors (malignant melanoma and basal cell carcinoma) and benign tumors (nevus, seborrhoeic keratosis, senile lentigo, and hematoma/hemangioma). We created the test dataset by randomly selecting 666 patients out of them and picking one image per patient, and created the training dataset by giving bounding-box annotations to the rest of the images (4732 images, 2885 patients). Subsequently, we trained a faster, region-based CNN (FRCNN) with the training dataset and checked the performance of the model on the test dataset. In addition, ten board-certified dermatologists (BCDs) and ten dermatologic trainees (TRNs) took the same tests, and we compared their diagnostic accuracy with FRCNN. For six-class classification, the accuracy of FRCNN was 86.2%, and that of the BCDs and TRNs was 79.5% (
= 0.0081) and 75.1% (
< 0.00001), respectively. For two-class classification (benign or malignant), the accuracy, sensitivity, and specificity were 91.5%, 83.3%, and 94.5% by FRCNN; 86.6%, 86.3%, and 86.6% by BCD; and 85.3%, 83.5%, and 85.9% by TRN, respectively. False positive rates and positive predictive values were 5.5% and 84.7% by FRCNN, 13.4% and 70.5% by BCD, and 14.1% and 68.5% by TRN, respectively. We compared the classification performance of FRCNN with 20 dermatologists. As a result, the classification accuracy of FRCNN was better than that of the dermatologists. In the future, we plan to implement this system in society and have it used by the general public, in order to improve the prognosis of skin cancer.
Abstract
In the eighth edition of the American Joint Committee on Cancer Staging Manual, several modifications were made for melanoma. These modifications were aimed at improving the prognosis ...prediction accuracy of the staging system. The main modifications are as follows: the cutoff value of the T1 category has been changed, and there are new classifications of stage IIID and of M1d (metastasis of the central nervous system). These changes will allow for more accurate stratification of melanoma prognosis. However, it is necessary to validate the new modifications through future clinical research.
We summarized the changes in the eighth edition of the American Joint Committee on Cancer Staging Manual for melanoma. These changes will allow for a more accurate stratification of melanoma prognosis.
Previous clinical trials indicate that 10%–25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not ...been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non‐common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3–86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1–17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p = 0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non‐common cancers (9.4%) (p = 0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non‐common cancers.
Genomically matched therapy after comprehensive genomic profiling (CGP) tests was administered to 12.2% of patients in clinical practice. We demonstrated the clinical utility of CGP tests in clinical practice, particularly among those with common cancers who received genomically matched therapy more frequently than those with non‐common cancers.
Cutaneous angiosarcomas is a rare cancer with poor prognoses. The common radiotherapy techniques that have been reported so far are two pairs of lateral X-ray and electron fields. However, it is ...quite difficult to irradiate scalp angiosarcomas (SAs) homogeneously with this technique. In this study, safety, effectiveness, and risk factors were assessed for localized SAs ≥ 5 cm treated with intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with boluses. Sixty-eight angiosarcoma patients who had received radiotherapy in our institution between January 2007 and November 2020 were retrieved from our radiotherapy database. Of these patients, 27 localized SA patients were included in the retrospective analysis. The 2-year overall survival, local progression-free rate, and distant metastases-free survival were 41.8%, 48.4%, and 33.1%. All the patients experienced acute radiation dermatitis ≥ grade 2, with18 (66.7%) ≥ grade 3. No nodule lesion was a significant unfavorable predictive factor of acute radiation dermatitis ≥ grade 3. Tumor bleeding at the initiation of radiotherapy and tumor invasion to the face were significant predictive factors of overall survival, and tumor bleeding at the initiation of radiotherapy was also a significant predictive factor of local progression-free rate.
Malignant melanoma (MM) is usually resistant to radiotherapy. Brachytherapy may be an option in patients with bleeding or pain, and those in whom surgery is difficult. Brachytherapy has few side ...effects and can be used in combination with external beam radiotherapy or chemotherapy. We summarize the demographic and clinical characteristics of 15 patients who received brachytherapy for MM at our hospital and describe two of these representative cases. Patient 1 had an approximately 10‐mm, dark‐red nodule near the external urethral meatus. Excision was not performed to preserve urethral function. A gradual improvement was observed after 48 Gy of remote afterloading system (RALS) brachytherapy and nivolumab therapy. Patient 2 had a 38‐mm, black tumor on the vagina. Post‐resection, RALS brachytherapy was administered to treat the residual black macule and a lesion quickly disappeared. In all 15 cases, nine patients received radiotherapy for local control and six patients received palliative radiotherapy to reduce symptoms such as bleeding and pain. The irradiation site was the vagina in six patients, lymph node metastasis in five, head and neck in two, skin or subcutaneous metastases in two, and the anus in one. Treatment effect for local control and palliative care was 75% and 83% of patients, respectively. In particular, disappearance of the tumor or disappearance of symptoms was observed in half of the cases of brachytherapy to the vagina. On the other hand, brachytherapy was not very effective for lymph node metastases. Immediately after radiotherapy, eight (53%) patients experienced dermatitis or mucositis. Due to the histological and structural characteristics of mucosal melanoma of the luminal organs, brachytherapy may be an effective therapy. Hence, widespread use of brachytherapy with an appropriate irradiation technique aiming for local control and palliative care in case of unresectable MM should be considered.
Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death‐1 protein, were suggested in previous phase 1 studies. The present phase 2, ...single‐arm study (JAPIC‐CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3‐week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression‐free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1‐ and 2‐year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3–4 drug‐related adverse events were observed in 31.4% of patients. Pretreatment serum interferon‐γ, and interleukin‐6 and ‐10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.
Repeated intravenous administration of nivolumab had potent and durable anti‐tumor effects and a manageable safety profile in advanced melanoma patients in Japan. Pre‐treatment serum cytokine profiles were suggested as correlates for predicting treatment efficacy.
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