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PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
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Aminopiridinas , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Piperazinas , Inibidores de Proteínas Quinases , Purinas , Piridinas , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Pessoa de Meia-Idade , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piridinas/uso terapêutico , Estudos Retrospectivos , Idoso , Piperazinas/uso terapêutico , Aminopiridinas/uso terapêutico , Purinas/uso terapêutico , Taiwan , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento , Metástase Neoplásica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo AsiáticoRESUMO
The aim of this study was to elucidate molecular profiling in HER2-low tumors based on a promising dataset. A total of 615 consecutive HER2-negative breast cancer samples were assayed. The genomic mutations in the two groups with different HER2 expression levels (HER2-0 vs. HER2-low) were compared. The mutation types obtained via next-generation targeted sequencing were correlated with the clinicopathological features of the patients with HER2-0 and HER2-low breast cancer. The results showed that there was a significantly higher percentage of receptor-positive (ER/PR) tumors and more low-level Ki-67 tumors, but a lower incidence of stage I/II tumors in the HER2-low group compared to the HER2-0 group. There was a significantly higher frequency of 17.62% (65/369) for PIK3CA_SNA in the HER2-low group than in the HER2-0 group, which had a frequency of only 9.35% (23/246) (p = 0.006). When the called gene alterations in the triple-negative breast cancer (TNBC) group were compared with those in the luminal-like breast cancer group, there was a significantly high frequency of 28.17% (140/497) for ERBB2_SNA in a luminal-like group than in the TNBC group(16.95% (20/118)).We conclude that the early detection of PIK3CA mutations is likely to be important and might help therapeutic decision making in patients with HER2-low tumors.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genômica , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
BACKGROUND: Despite the utilization of immune checkpoint inhibitors (ICIs) in treating numerous types of cancers being approved, their efficacy in tumor control in the clinic is not satisfactory. Since adoptive cell therapy (ACT) can alter the tumor microenvironment, we hypothesized that ACT potentially synergized with ICI in tumor control and examined this hypothesis via a murine allograft model. METHODS: Female C57BL/6 mice were stimulated with interleukin 15 and granulocyte monocyte-colony stimulating factor, followed by collecting their bone marrow cells for murine NKDC cultivation. Then, female C57BL/6 mice, inoculated with lymphoma cancer cell line E.G7-OVA, were administrated with murine NKDC cells, murine anti-program cell death ligand-1 antibody (α-mPD-L1), or both for 28 days. After 28 days of treatment, mice were sacrificed whose inoculated tumors, spleen, sentinel lymph nodes, and peripheral blood were collected to measure tumor size, lymphocyte infiltration, and change of immune cell profile. RESULTS: Combined treatment of NKDCs with α-mPD-L1 exhibited significantly stronger tumor control efficacy than treatment of NKDCs or α-mPD-L1 alone. NKDCs/α-mPD-L1 combination increased migration of dendritic cells, CD4, CD8 T cells, and activated CD8 T cells to the tumor-bedding site, and promoted endogenous tumor-specific cytotoxic T-cell response. CONCLUSION: The current study confirmed our hypothesis that combining NKDC ACT with ICI therapy can potentiate tumor control efficacy by manipulating the tumor microenvironment. This study provided a novel circumstance on tumor immunotherapy.
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Antígeno B7-H1 , Neoplasias , Feminino , Camundongos , Animais , Antígeno B7-H1/metabolismo , Camundongos Endogâmicos C57BL , Células Matadoras Naturais , Células Dendríticas , Aloenxertos/metabolismo , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
BACKGROUND: CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. METHODS: In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. CONCLUSION: Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.
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Neoplasias da Mama , Neutropenia , Piperazinas , Piridinas , Feminino , Humanos , Estudos Retrospectivos , Prevalência , Receptor ErbB-2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Neutropenia/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinase 4 Dependente de CiclinaRESUMO
BACKGROUND: The human epidermal growth factor receptor 2 (HER2) negative luminal B1 subtype of breast cancer has been reported with a poorer outcome than luminal A in recent studies. This study aimed to investigate the molecular alterations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of luminal B1 breast cancer in Taiwan. METHODS: We enrolled patients with luminal B1 breast cancer in our study. They were classified as patients who received curative surgery and adjuvant or neoadjuvant chemotherapy as the low-risk group, and who had advanced or metastatic disease or early relapse during the follow-up time as the high-risk group. Using targeted sequencing, we evaluated genomic alterations, interpreting variants with the ESMO Scale of clinical actionability of molecular targets (ESCAT). RESULTS: A total of 305 luminal B1 breast cancer patients underwent targeted sequencing analyses. The high-risk patients reported more actionable genes and called variants than the low-risk group (P < 0.05). PIK3CA (42%), FGFR1 (25%), and BRCA1/2 (10.5%) were the most prevalent ESCAT actionable alterations in luminal B1 breast cancer. There was no difference in the prevalence of actionable mutations between these two groups, except for ERBB2 oncogenic mutations, which were more prevalent among the high-risk than the low-risk group (P < 0.05). Alterations in PTEN, ERBB2, and BRCA1/2 were associated with disease relapse events in luminal B1 breast cancer. CONCLUSIONS: PIK3CA, FGFR1, and BRCA1/2 were the most prevalent actionable alterations among Taiwanese luminal B1 breast cancer. Moreover, PTEN and BRCA1/2 was significantly associated with disease relapse.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Proteína BRCA1/genética , Taiwan/epidemiologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Proteína BRCA2/genética , Genômica , Mutação , Recidiva , Classe I de Fosfatidilinositol 3-Quinases/genética , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
BACKGROUND: Thymic carcinoma is a rare disease with an incidence of around 0.5 cases per million with a poor prognosis. The aim of this study was to assess patient outcomes with advanced thymic carcinoma receiving first-line chemotherapy. METHODS: In our retrospective cohort study, we included patients who underwent treatment for metastatic thymic carcinoma between January 2013 to December 2019 in our hospital. Overall survival, progression-free survival (PFS), objective response rates (ORR) and chemotherapy regimens were assessed and analyzed. RESULTS: A total of 27 patients were retrospectively analyzed. All patients received a platinum (cisplatin or carboplatin) based regimen as first-line chemotherapy (29.6% received ADOC, 11.1% received PE, 40.7% received CP, 14.8% received CAP). The median PFS on first-line chemotherapy was 199 days. The response rate was 40.7%. Median overall survival (OS) was 585 days. Positive CD5 staining was associated with better PFS. CONCLUSION: We highlight the critical role of platinum-based chemotherapy agents as a primary treatment modality in advanced thymic carcinoma, underscoring the efficacy of platinum as a first-line option for recurrent disease, even in cases previously treated with platinum. Additionally, our findings indicate that CD5 positivity could be associated with improved PFS, suggesting its potential as a prognostic marker.
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Antineoplásicos , Timoma , Neoplasias do Timo , Humanos , Timoma/tratamento farmacológico , Timoma/patologia , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Platina/uso terapêutico , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (gBRCA1/2) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (sBRCA1/2) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1, BRCA2, and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. METHODS: A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. RESULTS: Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. CONCLUSION: Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.
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Proteína BRCA1 , Neoplasias da Mama , Humanos , Feminino , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Genes BRCA2 , Prevalência , Mutação em Linhagem Germinativa , Predisposição Genética para Doença , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , GenômicaRESUMO
In this study, we evaluated the concordance of targeted sequencing between paired ctDNA and matched tumor samples from early breast cancers treated with curative intention. Molecular profiling was performed using the Oncomine Comprehensive Assay v3 and the Oncomine Breast cfDNA Assay v2. The liquid biopsy detection rate was 39% (all-stage breast cancers, n = 612). Among 246 early-stage patients assayed for both ctDNA and matched tumor, the cfDNA assay detected 73 (29.6%) and the comprehensive assay detected 201 (81.7%) breast cancers with at least one alteration (χ2 test, p = 0.001). In total, 67 (25.6%) cases tested positive on both platforms, while the cfDNA and comprehensive assays detected an additional 10 (4%) and 138 (56%) cases, respectively. The most prevalent mutant genes were TP53 (68.3%) and KRAS (53.5%), while the PIK3CA (39.4%), AKT1 (45.9%), and ERBB2 (17.1%) mutations constituted biomarkers for FDA-approved therapeutics. Our study showed that tumor tissue should be the source of actionable mutation detection for early breast cancers, considering that the concordance rate between tumor and liquid biopsy was only one-quarter.
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Neoadjuvant chemotherapy (NACT)-induced pathologic complete response (pCR) is associated with a favorable prognosis for breast cancer. Prior research links tumor-infiltrating lymphocytes with breast cancer chemotherapy response, suggesting the tumor-immune microenvironment's role. The aim of this study was to evaluate the immune-related genes that exhibit associations with the response to NACT. In this study, we analyzed a total of 37 patients (aged 27-67) who received NACT as the first-line treatment for primary breast cancer, followed by surgery. This group consisted of nine patients (24.3 %) with estrogen receptor (ER)-positive/HER2-negative status, ten patients (27.0 %) with ER-positive/HER2-positive status, five patients (13.5 %) with ER-negative/HER2-positive status, and thirteen patients (35.1 %) with triple-negative breast cancer (TNBC). Among these patients, twelve (32.4 %) achieved a pCR, with eight (66.6 %) having HER2-positive tumors, and the remaining four having TNBC. To identify immune-related genes linked with pCR in subjects with breast cancer prior to NACT, we collected fresh tissues for next-generation sequencing. Patients with pCR had higher expressions of eight genes, KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1, and CA4, compared to non-pCR patients. The 8-gene signature was associated with good prognosis and linked to better relapse-free survival in patients receiving chemotherapy. The expression of these genes was involved in better drug response, displaying a positive correlation with the infiltration of immune cells. In conclusion, we have identified eight immune-related genes that are associated with a favorable prognosis and positive responses to drugs. This 8-gene signature could potentially provide prognostic insights for breast cancer patients undergoing NACT.
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Background: Breast cancer is the most common cancer type that affects women. In hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the most frequently mutated gene associated with poor prognosis. This study evaluated the frequency of PIK3CA mutations in the Taiwanese breast cancer population. Methodology: This is a retrospective study; patient data were collected for 2 years from a next-generation sequencing database linked to electronic health records (EHRs). The primary endpoint was the regional prevalence of PIK3CA mutation. The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment. Results: PIK3CA mutations were identified in 278 of 728 patients (38%). PIK3CA mutations were reported in 43% of patients with HR-/HER2+ subtype and 42% of patients with HR+/HER2- postmenopausal status. A lower prevalence of PIK3CA mutations was observed in triple-negative (27%) and HR+/HER2- premenopausal patients (29%). The most common mutation was at exon 20 (H1047R mutation, 41.6%), followed by exon 9 (E545K mutation, 18.9% and E542K mutation, 10.3%). Among patients treated with CDK4/6 inhibitors, the median time to treatment failure was 12 months (95% CI: 7-21 months) in the PIK3CA mutation cohort and 16 months (95% CI: 11-23 months) in the PIK3CA wild-type cohort, whereas patients receiving an mTOR inhibitor reported a median time to treatment failure of 20.5 months (95% CI: 8-33 months) in the PIK3CA mutation cohort and 6 months (95% CI: 2-9 months) in the PIK3CA wild-type cohort. Conclusion: A high frequency of PIK3CA mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of PIK3CA mutations might influence therapeutic decisions, leading to better treatment outcomes.
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Damage associated molecular patterns (DAMPs), including calreticulin (CRT) exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, characterize immunogenic cell death (ICD) and may play a role in cancer immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of breast cancer with higher lymphocyte infiltration. Here, we found that regorafenib, a multi-target angiokinase inhibitor previously known to suppress STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic murine model, regorafenib treatment increased HMGB1 and CRT expression in xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical staining revealed increased CD4+ and CD8+ tumor-infiltrating T cells in 4T1 xenografts following regorafenib treatment. Regorafenib treatment or programmed death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the proportion of MHC II high expression on dendritic cells in mice with smaller tumors, the combination of regorafenib and PD-1 blockade did not show a synergistic effect on anti-tumor activity. These results suggest that regorafenib induces ICD and suppresses tumor progression in TNBC. It should be carefully evaluated when developing a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor.
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Proteína HMGB1 , Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína HMGB1/farmacologia , Morte Celular , Trifosfato de Adenosina/farmacologia , Linhagem Celular TumoralRESUMO
PURPOSE: Trastuzumab, a potent anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is conditionally reimbursed by the Taiwan National Health Insurance (NHI) for HER2-positive breast cancer (BC). Trastuzumab-induced cardiotoxicity studies have well characterized heart failure (HF) but fewer addressed arrhythmia, particularly the association of potential life threatening atrial fibrillation (Af) is poorly characterized. We aimed to study the trastuzumab-related risk of Af and HF using the claimed data of Taiwan NHI. METHODS: A nationwide retrospective cohort of patients with BC from the Taiwan NHI reimbursement database from January 2007 to December 2016 was analyzed. Propensity score matching and competing risk model analysis were used for adjusting confounding concurrent medication or comorbidities and competing events. The HF study was used to validate the method used. RESULTS: For Af, 12,472 trastuzumab users were matched with 12,472 non-trastuzumab users. For HF, 12,241 trastuzumab users and 12,241 non-users were enrolled. We found that trastuzumab users had significantly worse HF-free survival but not Af-free survival than non-trastuzumab users. In the competing risk analysis, the use of trastuzumab did not increase the risk of Af (hazard ratio [HR] 0.76, P = 0.0006) but was associated with HF (HR 1.19, P = 0.0052). The risk trends among stratifications by comorbidities and concurrent medication remained in similar directions for both Af and HF. CONCLUSION: Trastuzumab in real-world practice was associated with an increased risk of HF, but was not associated with an increased risk of Af in BC patients. Trastuzumab-induced arrhythmogenic effects may be masked by concurrent heart-protecting measures, more prominent roles of comorbidities or concurrent medications under real-world settings. Further studies are required.
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Fibrilação Atrial , Neoplasias da Mama , Insuficiência Cardíaca , Humanos , Feminino , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Trastuzumab/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Estudos Retrospectivos , Pontuação de Propensão , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/epidemiologia , Medição de RiscoRESUMO
BACKGROUND: The prognosis of unfavorable cancer of unknown primary is extremely poor. This is the first report to compared the treatment results between generations of CUP and examined prognostic factors. METHODS: This retrospective single-center cohort study enrolled 68 patients with newly diagnosed unfavorable cancer of unknown primary at Taipei Veteran General Hospital from 2017 to 2020 as study cohort and 167 patients from 2000 to 2009 as historical cohort. RESULTS: The median overall survival was 4.3 months in the study cohort (95% CI, 2.7-6.2 months) and 4.5 months in the historical cohort (95% CI, 3.0-5.5 months; p = 0.858). Eleven patients in the study cohort received immunotherapy. The disease control rates were 45%. Multivariate analysis showed that an Eastern Cooperative Oncology Group score > 1 and a C-reactive protein level > 1 correlated with poor survival. A new prognostic stratification model was constructed by using Eastern Cooperative Oncology Group score and C-reactive protein values. The good-, intermediate-, and poor-risk groups had distinct median overall survival of 18.3, 7.0 and 1.2 months, respectively (area under the curve, 0.817; p < 0.001). CONCLUSION: The outcome of unfavorable cancer of unknown primary has not changed much over the last 20 years. The application of a new prognostic stratification model can further stratify unfavorable cancer of unknown primary.
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Neoplasias Primárias Desconhecidas , Humanos , Estudos de Coortes , Neoplasias Primárias Desconhecidas/terapia , Estudos Retrospectivos , Proteína C-Reativa , PrognósticoRESUMO
Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitinproteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins.MethodsWe performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts.ResultsWe uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C.ConclusionsOur study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer. (AU)
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Humanos , Aminopiridinas , Benzimidazóis , Neoplasias da Mama/patologia , Hormônios/uso terapêutico , Fosfatidilinositol 3-Quinases , Ubiquitinas/uso terapêutico , Purinas , RNA MensageiroRESUMO
Taxanes-containing chemotherapy constitutes an essential backbone for both early and metastatic breast cancer (mBC). However, the two major taxane drugs-paclitaxel and docetaxel-have distinct safety profiles. In this review, we summarize the safety outcome and management following treatment with both taxanes from selected clinical trials. We utilized PubMed to perform literature search before April 2021. Five phase III randomized controlled trials with reports of individual taxane adverse events (AEs) were included in this review. Grade 3/4 AEs were summarized and discussed extensively. The rates of grade 3/4 neutropenia were higher with docetaxel than with paclitaxel. For non-hematologic grade 3/4 AEs, peripheral neuropathy was more frequent with paclitaxel while fluid retention was more frequent with docetaxel. Compared to paclitaxel, docetaxel had a higher rate of grade 3/4 gastrointestinal AEs. Grade 3/4 myalgia were generally comparable between the two taxanes. Except for neutropenia, the incidence rate of grade 3/4 AEs of taxanes was generally manageable. Peripheral neuropathy was more common with paclitaxel while grade 3/4 neutropenia was more common with docetaxel.
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Breast cancer is one of the leading causes of cancer death in women, and although treatment outcome has substantially improved in the past decades, advanced or metastatic breast cancers still carry a poor prognosis. Gene amplification is one of the frequent genetic alterations in cancer, and oncogene amplification may be associated with cancer aggressiveness and oncogenicity. Targeting amplified genes such as HER2 has vastly improved disease outcome and survival, and anti-HER2 therapeutics have revolutionized the standard of care in HER2 breast cancer. Besides currently known druggable gene amplifications including ERBB2 and FGFR2, other frequently amplified genes are relatively less well known for function and clinical significance. By querying four large databases from TCGA and AACR-Genie, from a total of 11,890 patients with invasive ductal breast carcinoma, we discover IKZF3, CCND1, ERBB2 to be consistently amplified across different cohorts. We further identify IKZF3 as a frequently amplified gene in breast cancer with a prevalence of 12-15% amplification rate. Interestingly, IKZF3 amplification is frequently co-amplified with ERBB2/HER2, and is also associated with worse prognosis compared to IKZF3 non-amplified cancers. Analysis of HER2 breast cancer patients treated with trastuzumab revealed decrease in both ERBB2/HER2 and IKZF3 expression. Further investigation using the DepMap for gene dependency by genome-wide CRISPR screening revealed dependence on IKZF3 in HER2 breast cancer cell lines. Our study utilized an integrative analysis of large-scale patient genomics, transcriptomics and clinical data to reveal IKZF3 as a frequently amplified gene, and suggest a potential role of IKZF3 as a druggable target for HER2 breast cancer.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Amplificação de Genes , Humanos , Fator de Transcrição Ikaros/genética , Mutação , Prognóstico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêuticoRESUMO
PURPOSE: Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. METHODS: We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts. RESULTS: We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C. CONCLUSIONS: Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.
Assuntos
Neoplasias da Mama , Aminopiridinas , Benzimidazóis , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Feminino , Hormônios/uso terapêutico , Humanos , Fosfatidilinositol 3-Quinases , Complexo de Endopeptidases do Proteassoma/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas , RNA Mensageiro , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinas/uso terapêuticoRESUMO
PURPOSE: Deleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations. METHODS: We evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues. RESULTS: Among 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes. CONCLUSIONS: The prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.