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Background: Globally, gastric cancer holds the fifth position in terms of prevalence among malignant tumors and is the fourth leading cause of cancer-related mortality. Particular attention should be paid to cardia adenocarcinoma (CA) due to its increasing incidence and poor prognosis. Diagnosis of CA frequently occurs in advanced stages because of its late symptoms. In such cases, neoadjuvant chemotherapy is the primary treatment option. The response to chemotherapy depends on multiple variables including the tumor's molecular profile, the patient's performance status, and the feasibility of using targeted therapy. Patients exhibiting an exceptional response, defined as a complete response to medical therapy lasting more than 1 year, or a partial response or stable disease lasting more than 2 years, are rarely described. This case report presents one of the longest-lasting exceptional responses to chemotherapy in metastatic cardia adenocarcinoma and discusses its clinical implications. Case presentation: A 49-year-old male patient presented with cardia adenocarcinoma (human epidermal growth factor receptor 2 negative, mismatch repair proficient) and liver metastases. Molecular profiling identified a pathogenic mutation in the TP53 gene (R123W; Arg123Trp) as the sole alteration found. Five months after initiating the neoadjuvant chemotherapy with fluorouracil-leucovorin-oxaliplatin-docetaxel, the patient achieved a complete clinical response. The molecular profile was compared with others previously documented in an international data portal, revealing a similar pattern. At 4 years and 3 months from diagnosis, the exceptional response was still confirmed. The patient underwent a cumulative number of 33 cycles of chemotherapy, leading to chemotherapy-induced liver damage. Conclusions: Exceptional responses to neoadjuvant chemotherapy in cardia adenocarcinomas are rarely reported. The documentation of exceptional responses to cancer therapies should be included in large data repositories to explore the molecular fingerprint of these tumors. In such cases, the clinical implications of long-term chemotherapy should always be taken into account.
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Immunotherapy with PD-1 inhibitors monotherapy or combined with chemotherapy comprises the first-line palliative treatment for patients with recurrent or metastatic head and neck squamous cell cancers (R/M HNSCC). The established survival advantage among responders is overshadowed by the high percentage of patients failing the standard PD-1 inhibitor-based treatments. Salvage therapies are direly needed. However, no current standards are available. We present the case of a 65-year-old patient with heavily pretreated laryngeal squamous cell carcinoma who had an exceptional response to cetuximab monotherapy following the failure of immunotherapy with the PD-1 inhibitor nivolumab. We reviewed the literature for other cases of exceptional response to cetuximab, clinical studies investigating the combined or sequential administration of cetuximab and PD-1 inhibitors, and the mechanistic rationale for consideration of cetuximab as a potential salvage treatment after immunotherapy with PD-1 inhibitors. In addition to the specific epidermal growth factor receptor inhibitory effect, cetuximab, as an immunoglobulin G1 isotype, binds NK cells and elicits antibody-dependent cellular toxicity, triggering a domino of immunostimulatory, and immunoinhibitory effects that actually might decrease the cetuximab anticancer efficacy. However, in a tumor microenvironment exposed to previous treatment with a PD-1 inhibitor, the effects of the PD-1 inhibitor followed by cetuximab on innate and adaptative immune response appear to synergize. Specifically, persistent immune checkpoint inhibitors' consequences may negate downstream immunosuppressive effects of cetuximab caused through PD-1/PD-L1 upregulation, making it a more potent treatment option. Besides the potential synergistic effect on antitumor immune response with previous immune checkpoint inhibitors therapy, cetuximab is the only targeted agent approved for treating R/M HNSCC, making it a most advantageous candidate for further treatment validation studies as salvage treatment post-immunotherapy.
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BACKGROUND: Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response. METHODS: Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders). RESULTS: We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder. CONCLUSION: Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed.
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INTRODUCTION: The Exceptional Responders Initiative (ERI) at the National Cancer Institute attempts to correlate unusually good outcomes in patients with cancer with genetic targets in tumors and the therapies the patients received. It is not known if other factors might contribute to exceptional responses or outcomes. We explored aspects of the medical history, lifestyle changes, complementary and alternative medicine (CAM) use and communication between health care practitioners and patients who experienced an exceptional response following cancer treatment. METHODS: All subjects whose case was submitted to the ERI were eligible to participate in the survey. A 121-question survey questionnaire was developed to assess aspects of the subject's past medical history, lifestyle (e.g., diet, exercise, spirituality) and use of CAM. RESULTS: Thirty subjects completed and returned the questionnaire from approximately 88 patients invited to participate (approximate response rate = 34%). Approximately 68% were female and 32% were male. Fifty percent of subjects changed their diet after their cancer diagnosis. Eighteen patients (60%) reported using a CAM therapy (not including oral vitamins/minerals or spiritual practices) during their Exceptional Response (ER). CONCLUSION: Multiple factors, including features of the tumor itself, the patient, or the environment, could affect tumor response or patient survival, either solely or in combination with the treatments received. Many patients use other medications, change their diet or physical activity or use CAM interventions after their cancer diagnosis. Investigators attempting to understand the exceptional response phenomenon should acquire rich data sets of their subjects that include information about these factors.
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Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer. Tumor characteristics typically feature estrogen receptor, progesterone receptor, and HER2-negative, triple-negative breast cancer (TNBC), with a poorer prognosis relative to pure invasive ductal or lobular disease. Resistance to chemotherapy often leads to local recurrence and distant metastasis. Genomic profiling has identified multiple molecular abnormalities that may translate to targetable therapies in MBC. These tumors are known to display higher PD-L1 expressivity than other subtypes of breast cancer, and disease control with pembrolizumab and chemotherapy has been documented. We identify a patient with metastatic, metaplastic TNBC, with mesenchymal components and osseous differentiation, who completed 2 years of pembrolizumab treatment and has remained without evidence of disease after 32 months of observation, while maintaining good quality of life. Future efforts should focus on immunotherapy response with respect to the various subtypes of MBC, and treatment should continue to be incorporated in clinical trials to maximize disease response.
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A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
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Antineoplásicos/uso terapêutico , Redes Reguladoras de Genes , Variação Genética , Genômica/métodos , Neoplasias/tratamento farmacológico , Biópsia , Epigênese Genética , Feminino , Humanos , Masculino , Neoplasias/genética , Neoplasias/patologia , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Microambiente TumoralRESUMO
OBJECTIVES: Anti-PD-1 immune checkpoint blockade represents the onset of a new era in cancer immunotherapy. However, robust predictors are necessary for screening patients with immune checkpoint-responsive oesophageal squamous cell carcinoma (ESCC). METHODS: We obtained biopsy samples from an ESCC patient with mixed responses. The expression of CD4, CD8, CD68, PD-L1, RBPJL and IL-16 was analysed by immunohistochemistry, and the correlation with prognostic value was obtained from the GEPIA portal. T-cell functions were examined by flow cytometry, MTS and transwell assays. The secreted cytokines were identified using an Inflammation Array Kit. The concentration of soluble IFN-γ was measured by enzyme-linked immunosorbent assay. The clinical benefit of RBPJL was examined in a PBMC xenograft mouse model. RESULTS: The patient had an exceptional clinical response with shrinkage of the primary oesophageal and lung metastatic lesions as well as enlargement of liver metastatic lesions after toripalimab monotherapy. Four liver-specific gene mutations were identified. RBPJL showed better response to toripalimab in the PBMC cell-derived xenograft (CDX) ESCC model. Conditional medium from RBPJL overexpression induced chemotaxis and proliferation of T lymphocytes, as well as Th2/Th1 differentiation through the RBPJL-NF-κB-IL-16 axis in vitro. These functions were all inhibited by the p.P476S mutation of RBPJL (RBPJL (p.P476S)). CONCLUSIONS: We report for the first time that RBPJL (p.P476S) promotes tumor growth in ESCC and inhibits the efficacy of anti-PD-1 therapy through blunting T-cell responses. Our findings provide a potential new predictor for evaluating the efficacy of anti-PD-1 therapy in ESCC patients.
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BACKGROUND: For luminal metastatic breast cancer (MBC), endocrine therapy (ET) is the recommended initial treatment before chemotherapy. Our objective was to evaluate the efficacy of multiple ET lines in a real-life study. METHODS: The Breast Cancer Epidemiological Strategy and Medical Economics (ESME) project analysed data from all patients with systemic treatment for MBC initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. The primary end-point was the successive progression-free survival (PFS) evaluation. RESULTS: The ESME research programme included 9921 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (HER2-) MBC. Before any chemotherapy, 4195 (43.4%), 1252 (29.8%) and 279 (6.6%) patients received one, two or three ET ± targeted therapy, respectively. The median PFS for first-, second- and third-line ET ± targeted therapy was 11.5 (95% confidence interval [CI], 10.8-12.1), 5.8 (95% CI, 5.3-6.1) and 5.5 (95% CI, 4.6-6.3) months, respectively. In a multivariate analysis, time from diagnosis to metastatic recurrence (P < 0.0001), presence of symptoms at metastatic relapse (P = 0.01), number of metastatic sites (P = 0.0003) and their localisation (P < 0.0001) were prognostic factors for PFS1. Duration of previous PFS was the only prognostic factor for subsequent PFS (10% threshold). Ten percent of the patients showed long-term response to ET, with a total treatment duration before chemotherapy ≥43.6 months. CONCLUSIONS: Median PFS in our HR+/HER2- real-life cohort is similar to median first-line PFS reported in clinical trials, regardless of ET used as second- and third-line treatment. Despite the international consensus on early initiation of ET, the latter is not prescribed in most of the cases. Patients with a low tumour burden may achieve prolonged response on ET.
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Antineoplásicos Hormonais/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , França , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
Curative therapy for cancer patients with advanced-stage disease remains elusive. While rare outlier responses to anticancer therapies exist, barriers limit our understanding of the molecular and genetic basis of such profound, life-altering responses. Here, we describe how phenotype-to-genotype studies are elucidating the molecular underpinnings of outlier responses and informing strategies to extend such unprecedented sensitivity to broader molecularly defined patient populations.
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Biomarcadores Farmacológicos , Biomarcadores Tumorais/genética , Neoplasias/tratamento farmacológico , Medicina de Precisão , Estudos de Associação Genética , Predisposição Genética para Doença , Genômica , Humanos , Terapia de Alvo Molecular , Neoplasias/genéticaRESUMO
Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p = 0.039). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.
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Resistencia a Medicamentos Antineoplásicos/genética , Leiomiossarcoma/patologia , PTEN Fosfo-Hidrolase/genética , Neoplasias Uterinas/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/genética , Pessoa de Meia-Idade , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transcriptoma , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genéticaRESUMO
BACKGROUND: Metastatic head and neck squamous cell carcinoma (HNSCC) carries a very poor prognosis. A better understanding of the molecular driver of the disease and the identification of biomarkers of response remain paramount for an effective personalized therapy. CASE REPORT: We report an original case of a 56-year-old patient diagnosed with metastatic HNSCC to both kidneys, who experienced a long-lasting complete response to a single-agent cetuximab, a monoclonal antibody-targeting EGFR. Comprehensive multiplatform biomarker analysis of the tumor revealed the presence of phosphatidyl-inositol 3 kinase mutation, EGFR overexpression, and the absence of PD-1/PD-L1 expression. Since PI3K, a downstream effector of EGFR, is activated, the tumor regression may have occurred mainly through a cetuximab-induced immune-mediated response, rather than EGFR signal blockade. It is plausible that this effect was enhanced by the lack of PD-1 and PD-L1 expression. CONCLUSION: Our case proposes that the absence of PD-1 and PD-L1 expression in conjunction with EGFR overexpression may correlate with better response to cetuximab in HNSCC. This hypothesis needs to be examined through a large clinical trial.