Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to p...Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.展开更多
A 68-year-old man with left chest pain accompanied by chest tightness was reported.The computed tomography revealed a massive liver mass.Genetic and pathological tests confirmed advanced squamous cell lung carcinoma w...A 68-year-old man with left chest pain accompanied by chest tightness was reported.The computed tomography revealed a massive liver mass.Genetic and pathological tests confirmed advanced squamous cell lung carcinoma with the mutation of breast cancer susceptibility gene 1 and liver metastasis.The primary lung lesions and local liver metastases were well controlled through combined immunotherapy,antiangiogenic medications and Poly ADP-ribose polymerase inhibitors.Considering the high tumor load and the generally poor condition of the patient,transarterial chemoembolization,in place of the conventional chemotherapy treatment mode was chosed for liver metastasis in the current case.We discussed selecting a tailored program and outlined the patient’s diagnosis and treatment process.Additionally mentioned multiple drug combination strategies for squamous lung cancer.展开更多
Metastatic triple negative breast cancer(TNBC)has an aggressive phenotype with a predilection for visceral organs and brain.Best responses to chemotherapy are predominately in the first line.Recent studies have demons...Metastatic triple negative breast cancer(TNBC)has an aggressive phenotype with a predilection for visceral organs and brain.Best responses to chemotherapy are predominately in the first line.Recent studies have demonstrated improved progression free survival with the combination of atezolizumab/pembrolizumab and chemotherapy in programmed death-ligand 1 positive metastatic TNBC.However,a recent trial in a similar population showed no benefit for atezolizumab and paclitaxel which led to a Food and Drug Administration alert.Two phase III trials(OLYMPIAD and BROCADE3)demonstrated a benefit in progression free survival(PFS)but not overall survival in patients with BRCAassociated metastatic TNBC treated with Olaparib or Talazoparib respectively.For those treated with Talazoparib,the time to deterioration in health related-quality of life was also longer compared to chemotherapy.The BROCADE3 trial demonstrated that the combination of a platinum and veliparib increased PFS in first-line metastatic TNBC but at the cost of increased toxicity.There are no headto-head comparisons of a poly(adenosine diphosphate-ribose)polymerase inhibitors(PARPi)and platinums.There are unanswered questions regarding the role of PARPi maintenance after platinum therapy as is standard of care in BRCAassociated ovarian cancer.Other areas of therapeutic interest include targeting aberrations in the phosphoinositide 3-kinase pathway,protein kinase B,mammalian target of rapamycin or utilising antibody drug conjugates.This review focusses on recent and emerging therapeutic options in metastatic TNBC.We searched PubMed,clinicaltrials.gov and recent international meetings from American Society of Clinical Oncology,San Antonio Breast Cancer Conference and the European Society of Medical Oncology.展开更多
Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease.Recently,patients with germline BRCA mutations have received increased attention due to advances in t...Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease.Recently,patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors.Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8%of patients with sporadic pancreatic cancer.In patients with germline BRCA mutations,platinum-based chemotherapies and poly(ADP-ribose)polymerase inhibitors are effective treatment options which may offer survival benefits.This review will focus on the molecular biology,epidemiology,and management of BRCA-mutated pancreatic cancer.Further-more,we will discuss future directions for this area of research and promising active areas of research.展开更多
Small-cell lung cancer(SCLC)is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors.At present,radiotherapy and chemotherapy remain the mainstay of treatment for SCLC.Progress in targe...Small-cell lung cancer(SCLC)is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors.At present,radiotherapy and chemotherapy remain the mainstay of treatment for SCLC.Progress in targeted therapies for SCLC with driver mutations has been slow,and these therapies are still under investigation in preclinical or early-phase clinical trials,and research on antiangiogenic tyrosine kinase inhibitors(e.g.,anlotinib)has achieved some success.Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy.In this article we review the recent advances in immunotherapy for SCLC.展开更多
In this editorial,we comment on pancreatic cancer(PC),one of the most aggressive and lethal cancers.Only minimal improvements in survival rates have been achieved over recent years.Available chemotherapeutic regimens ...In this editorial,we comment on pancreatic cancer(PC),one of the most aggressive and lethal cancers.Only minimal improvements in survival rates have been achieved over recent years.Available chemotherapeutic regimens have little impact,and surgical resection remains the only reliable curative approach.We address current treatment options for these patients,focusing on the usefulness of breast cancer(BRCA)gene mutation as a prognostic biomarker and predictor of response to chemotherapy.Superior survival outcomes have been reported in patients with PC and mutant BRCA gene treated with first-line platinum-based chemotherapy.Therefore,it appears appropriate to include BRCA gene status among clinical criteria used to select the chemotherapy regimen.In addition,maintenance treatment with poly(ADP-ribose)polymerase inhibitors has been found to improve progression-free survival in patients with PC and mutated BRCA whose disease does not progress after first-line platinum-based chemotherapy.This combination has therefore been proposed as the optimal treatment regimen for these patients.展开更多
BACKGROUND Pancreatic acinar cell carcinoma(PACC)is a rare tumor.Up to 45%of PACCs have alterations in the DNA damage repair pathway and 23%harbor rearrangements in the BRAF or RAF1 genes.We present a PACC case with a...BACKGROUND Pancreatic acinar cell carcinoma(PACC)is a rare tumor.Up to 45%of PACCs have alterations in the DNA damage repair pathway and 23%harbor rearrangements in the BRAF or RAF1 genes.We present a PACC case with a germline BRCA2 likely pathogenic variant(LPV)to highlight the impact of genomic testing on treatment decisions and patient outcomes.In our larger case series,we provide clinic-based information on additional 10 PACC patients treated in our center.CASE SUMMARY A 70-year-old male was diagnosed with advanced PACC.At presentation,he was cachectic with severe arthralgia despite prednisolone and a skin rash that was later confirmed to be panniculitis.He was treated with modified FOLFIRINOX(mFFX)with the knowledge of the germline BRCA2 LPV.Following 11 cycles of mFFX,a computed tomography(CT)scan demonstrated significant tumor response in the pancreatic primary and hepatic metastases,totaling 70%from baseline as per Response Evaluation Criteria in Solid Tumors.Resolution of the skin panniculitis was also noted.We identified two additional PACCs with druggable targets in our case series.Our data contribute to practical evidence for the value of germline and somatic profiling in the management of rare diseases like PACC.CONCLUSION This patient and others in our larger case series highlight the importance of genomic testing in PACC with potential utility in personalized treatment.展开更多
BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer,while their role in gastrointestinal(GI)malignancies such as colorectal cancer(CRC),gastric cancer and oesophagea...BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer,while their role in gastrointestinal(GI)malignancies such as colorectal cancer(CRC),gastric cancer and oesophageal cancer(OeC)is still not well established.The main objective of this review is to summarise the available evidence on this matter.The studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these malignancies.Our review suggests that BRCA1/2 might have a role as a risk factor for colorectal,gastric and OeC,albeit with differences among these diseases:In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and OeC.Early-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these mutations.The assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds,where it is expected that a higher probability of response should be seen.A few clinical trials focused on poly(ADPribose)polymerase inhibitors use in GI cancers are currently ongoing.展开更多
BACKGROUND In recent years,targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer(NSCLC).However,the clinical evidence for successful off-label use o...BACKGROUND In recent years,targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer(NSCLC).However,the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.CASE SUMMARY We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation.He received gefitinib combined with six cycles of vinorelbine,cisplatin,and recombinant human endostatin as the first-line therapy.Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy,resulting in a progression-free survival(PFS)of 14 mo.Chemoradiotherapy was added following progression(enlarged brain metastases)on maintenance treatment.Unfortunately,the brain lesions were highly refractory and progressed again after 15 mo,at which time next-generation sequencing(NGS)of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations.NGS revealed that the patient harbored a BRCA2 germline mutation,the EGFR exon 19 deletion mutation disappeared,and no additional targetable genetic variant was detected.Therefore,the patient received olaparib combined with gefitinib and recombinant human endostatin,with a rapid and long-lasting clinical response(PFS=13.5 mo).CONCLUSION This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment,suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.展开更多
In late Dec.2019,a huge number of pneumonia cases caused by novel coronavirus were reported in China.2019-nCoV pandemic has influenced on millions of people's life across the world.This novel coronavirus was ident...In late Dec.2019,a huge number of pneumonia cases caused by novel coronavirus were reported in China.2019-nCoV pandemic has influenced on millions of people's life across the world.This novel coronavirus was identified to be similar with MERS and SARS.Therefore,researchers and academicians across the world still trying to find out vaccines,new drug molecules against SARS-CoV-2.The principle point of this review article is to explain the activity of favipiravir in preventing COVID-19.In view of constrained data available in the literature,we specify that favipiravir treatment,among all other anti-viral drugs,accompanied by oxygen inhalation therapy,maintaining fluid and electrolyte balance,and nutritional support may be helpful in fighting COVID-19.Researches were done on already approved existing anti-viral drugs for treating ebola virus,influenza virus infection and many such anti-viral agents like favipiravir,ritonavir,remdesivir,ribavirin,oseltamivir shows promising results in preventing COVID-19 infection and their clinical trials are currently undergoing in order to discover proper treatment of COVID-19.Among the aforementioned drug candidates,a broad-spectrum RNA polymerase inhibitor favipiravir,which demonstrated a promising tolerance profile and anti-viral efficacy in patients having COVID-19 manifestations.展开更多
The global burden of ovarian cancer is gradually increasing while patients still suffer from relatively limited treatment options.With recent advances in the decoding of the molecular landscape of ovarian cancer,more ...The global burden of ovarian cancer is gradually increasing while patients still suffer from relatively limited treatment options.With recent advances in the decoding of the molecular landscape of ovarian cancer,more options in targeted strategy were offered and can therefore be tailored in different clinical settings for individual patient.Targeting of the abnormal angiogenesis process is the first significant clinical breakthrough which revolutionized the treatment of advanced ovarian cancer,followed by the advent of poly-(ADP)-ribose polymerase(PARP)inhibitors.These two strategies represented by bevacizumab and olaparib respectively underwent tests of numerous clinical trials.In recent years,immune checkpoint inhibitors(ICIs)have been incorporated into the blueprint of ovarian cancer treatment though the effectiveness still left much to be desired.Herein,we systematically outlined recent advances in targeted therapy for ovarian cancer and summarized the landmark clinical trials for each targeted therapy including angiogenesis inhibitors,PARP inhibitors and ICIs.展开更多
Triple-negative breast cancer(TNBC),which accounts for approximately 15%of breast cancers(BCs)is characterized by a lack of expression of the hormone receptors(HRs)(estrogen receptor(ER)and progesterone receptor(PR)),...Triple-negative breast cancer(TNBC),which accounts for approximately 15%of breast cancers(BCs)is characterized by a lack of expression of the hormone receptors(HRs)(estrogen receptor(ER)and progesterone receptor(PR)),and human epidermal growth factor receptor 2(HER2).TNBC reveals very aggressive behavior and often leads to poor prognosis.Unfortunately,standard chemotherapy(CHT)is related to low response rates and short progression-free survival(PFS)in patients with metastatic TNBC,creating an unmet need.However,recent recognition of different molecular subtypes and mutations within TNBC has allowed exploring some innovative targeted therapies,bringing new hope for women suffering from TNBC.Currently,some promising systemic treatment options in this area have been developed,including targeted therapies,such as poly(ADP-ribose)polymerase(PARP)inhibitors,immune checkpoint inhibitors,antibody-drug conjugates,and AKT inhibitors.The aim of this mini-review is to address these novel treatment modalities and highlight the main directions for further research and clinical practice in the advanced or metastatic forms of TNBC.This article presents poly(ADP-ribose)polymerase(PARP)inhibitors(e.g.,olaparib,talazoparib,and valaparib for treatment of BRCA-mutated,HER2-negative metastatic BC),immune checkpoint inhibitors(atezolizumab and pembrolizumab),an antibody-drug conjugate(ADC)(sacituzumab govitecan),and AKT inhibitors(ipatasertib and capivasertib).A brief outline of the main clinical trials leading to the approval of these new medications has been provided.Moreover,this overview discusses the efficacy and safety of these innovative treatment options,focusing on women with metastatic TNBC.In addition,this paper comments on some recent considerations,regarding avenues of delivering care and conduct clinical trials in patients with BC,during the COVID-19 pandemic.展开更多
Background:Metastatic triple-negative breast cancer(mTNBC)is an aggressive histological subtype with poor prognosis.Several first-line treatments are currently available for mTNBC.This study conducted a network meta-a...Background:Metastatic triple-negative breast cancer(mTNBC)is an aggressive histological subtype with poor prognosis.Several first-line treatments are currently available for mTNBC.This study conducted a network meta-analysis to compare these first-line regimens and to determine the regimen with the best efficacy.Methods:A systematic search of PubMed,EMBASE,the Cochrane Central Register of Controlled Bases,and mi-nutes of major conferences was performed.Progression-free survival(PFS),overall survival(OS),and objective response rate(ORR)were analyzed via network meta-analysis using the R software(R Core Team,Vienna,Austria).The efficacy of the treatment regimens was compared using hazard ratios and 95%confidence intervals.Results:A total of 29 randomized controlled trials involving 4607 patients were analyzed.The ranking was based on the surface under the cumulative ranking curve.Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR.For programmed death-ligand 1(PD-L1)and breast cancer susceptibility gene(BRCA)mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib was superior to docetaxel plus capecitabine.No significant difference was observed among the treatments in Os.Neutropenia,diarrhea,and fatigue were common serious adverse events.Conclusion:Cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC.For PD-L1 and BRCA mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option,Neutropenia,diarrhea,and fatigue are frequently occurring serious adverseevents.展开更多
Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences i...Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences in clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging mechanisms of resistance, and key clinical questions for future development.展开更多
Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency(HRD).HRD is found in a subgroup of cancer patients for several tumor types,and it has a clinical relevance to cance...Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency(HRD).HRD is found in a subgroup of cancer patients for several tumor types,and it has a clinical relevance to cancer prevention and therapies.Accumulating evidence has identified HRD as a biomarker for assessing the therapeutic response of tumor cells to poly(ADP-ribose)polymerase inhibitors and platinum-based chemotherapies.Nevertheless,the biology of HRD is complex,and its applications and the benefits of different HRD biomarker assays are controversial.This is primarily due to inconsistencies in HRD assessments and definitions(gene-level tests,genomic scars,mutational signatures,or a combination of these methods)and difficulties in assessing the contribution of each genomic event.Therefore,we aim to review the biological rationale and clinical evidence of HRD as a biomarker.This review provides a blueprint for the standardization and harmonization of HRD assessments.展开更多
Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break(DSB)signaling.P53-binding protein 1(53BP1)plays a critical role in coordinating the DSB repair pathway c...Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break(DSB)signaling.P53-binding protein 1(53BP1)plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining(NHEJ)-mediated DSB repair pathway that rejoins DSB ends.New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination(HR)signaling.This review focuses on the up-and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair,which in turn promotes the sensitivity of poly(ADP-ribose)polymerase inhibitor(PARPi)in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.展开更多
Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies.Although initial response to therapy is observed,recurrence and ultimate...Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies.Although initial response to therapy is observed,recurrence and ultimately chemoresistance result in overall therapeutic failure.This pattern has been evident with platinum therapy since the 1980s.Significant excitement surrounded the approval of poly(ADP-ribose)polymerase inhibition(PARPi)as a novel therapeutic option,especially with the advent of personalized medicine,but resistance has similarly developed to these treatments.Novel agents are constantly being sought,but if the obstacle of chemoresistance remains,the durability of responses will remain tenuous.Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured.Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.展开更多
基金Supported by The Ministry of Science and Higher Education of the Russian Federation,No.075-15-2020-789.
文摘Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.
文摘A 68-year-old man with left chest pain accompanied by chest tightness was reported.The computed tomography revealed a massive liver mass.Genetic and pathological tests confirmed advanced squamous cell lung carcinoma with the mutation of breast cancer susceptibility gene 1 and liver metastasis.The primary lung lesions and local liver metastases were well controlled through combined immunotherapy,antiangiogenic medications and Poly ADP-ribose polymerase inhibitors.Considering the high tumor load and the generally poor condition of the patient,transarterial chemoembolization,in place of the conventional chemotherapy treatment mode was chosed for liver metastasis in the current case.We discussed selecting a tailored program and outlined the patient’s diagnosis and treatment process.Additionally mentioned multiple drug combination strategies for squamous lung cancer.
文摘Metastatic triple negative breast cancer(TNBC)has an aggressive phenotype with a predilection for visceral organs and brain.Best responses to chemotherapy are predominately in the first line.Recent studies have demonstrated improved progression free survival with the combination of atezolizumab/pembrolizumab and chemotherapy in programmed death-ligand 1 positive metastatic TNBC.However,a recent trial in a similar population showed no benefit for atezolizumab and paclitaxel which led to a Food and Drug Administration alert.Two phase III trials(OLYMPIAD and BROCADE3)demonstrated a benefit in progression free survival(PFS)but not overall survival in patients with BRCAassociated metastatic TNBC treated with Olaparib or Talazoparib respectively.For those treated with Talazoparib,the time to deterioration in health related-quality of life was also longer compared to chemotherapy.The BROCADE3 trial demonstrated that the combination of a platinum and veliparib increased PFS in first-line metastatic TNBC but at the cost of increased toxicity.There are no headto-head comparisons of a poly(adenosine diphosphate-ribose)polymerase inhibitors(PARPi)and platinums.There are unanswered questions regarding the role of PARPi maintenance after platinum therapy as is standard of care in BRCAassociated ovarian cancer.Other areas of therapeutic interest include targeting aberrations in the phosphoinositide 3-kinase pathway,protein kinase B,mammalian target of rapamycin or utilising antibody drug conjugates.This review focusses on recent and emerging therapeutic options in metastatic TNBC.We searched PubMed,clinicaltrials.gov and recent international meetings from American Society of Clinical Oncology,San Antonio Breast Cancer Conference and the European Society of Medical Oncology.
文摘Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease.Recently,patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors.Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8%of patients with sporadic pancreatic cancer.In patients with germline BRCA mutations,platinum-based chemotherapies and poly(ADP-ribose)polymerase inhibitors are effective treatment options which may offer survival benefits.This review will focus on the molecular biology,epidemiology,and management of BRCA-mutated pancreatic cancer.Further-more,we will discuss future directions for this area of research and promising active areas of research.
文摘Small-cell lung cancer(SCLC)is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors.At present,radiotherapy and chemotherapy remain the mainstay of treatment for SCLC.Progress in targeted therapies for SCLC with driver mutations has been slow,and these therapies are still under investigation in preclinical or early-phase clinical trials,and research on antiangiogenic tyrosine kinase inhibitors(e.g.,anlotinib)has achieved some success.Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy.In this article we review the recent advances in immunotherapy for SCLC.
基金by Junta de Andalucía,No.PC-0498-2017 and No.PC-0549-2017.
文摘In this editorial,we comment on pancreatic cancer(PC),one of the most aggressive and lethal cancers.Only minimal improvements in survival rates have been achieved over recent years.Available chemotherapeutic regimens have little impact,and surgical resection remains the only reliable curative approach.We address current treatment options for these patients,focusing on the usefulness of breast cancer(BRCA)gene mutation as a prognostic biomarker and predictor of response to chemotherapy.Superior survival outcomes have been reported in patients with PC and mutant BRCA gene treated with first-line platinum-based chemotherapy.Therefore,it appears appropriate to include BRCA gene status among clinical criteria used to select the chemotherapy regimen.In addition,maintenance treatment with poly(ADP-ribose)polymerase inhibitors has been found to improve progression-free survival in patients with PC and mutated BRCA whose disease does not progress after first-line platinum-based chemotherapy.This combination has therefore been proposed as the optimal treatment regimen for these patients.
文摘BACKGROUND Pancreatic acinar cell carcinoma(PACC)is a rare tumor.Up to 45%of PACCs have alterations in the DNA damage repair pathway and 23%harbor rearrangements in the BRAF or RAF1 genes.We present a PACC case with a germline BRCA2 likely pathogenic variant(LPV)to highlight the impact of genomic testing on treatment decisions and patient outcomes.In our larger case series,we provide clinic-based information on additional 10 PACC patients treated in our center.CASE SUMMARY A 70-year-old male was diagnosed with advanced PACC.At presentation,he was cachectic with severe arthralgia despite prednisolone and a skin rash that was later confirmed to be panniculitis.He was treated with modified FOLFIRINOX(mFFX)with the knowledge of the germline BRCA2 LPV.Following 11 cycles of mFFX,a computed tomography(CT)scan demonstrated significant tumor response in the pancreatic primary and hepatic metastases,totaling 70%from baseline as per Response Evaluation Criteria in Solid Tumors.Resolution of the skin panniculitis was also noted.We identified two additional PACCs with druggable targets in our case series.Our data contribute to practical evidence for the value of germline and somatic profiling in the management of rare diseases like PACC.CONCLUSION This patient and others in our larger case series highlight the importance of genomic testing in PACC with potential utility in personalized treatment.
文摘BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer,while their role in gastrointestinal(GI)malignancies such as colorectal cancer(CRC),gastric cancer and oesophageal cancer(OeC)is still not well established.The main objective of this review is to summarise the available evidence on this matter.The studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these malignancies.Our review suggests that BRCA1/2 might have a role as a risk factor for colorectal,gastric and OeC,albeit with differences among these diseases:In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and OeC.Early-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these mutations.The assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds,where it is expected that a higher probability of response should be seen.A few clinical trials focused on poly(ADPribose)polymerase inhibitors use in GI cancers are currently ongoing.
文摘BACKGROUND In recent years,targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer(NSCLC).However,the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.CASE SUMMARY We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation.He received gefitinib combined with six cycles of vinorelbine,cisplatin,and recombinant human endostatin as the first-line therapy.Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy,resulting in a progression-free survival(PFS)of 14 mo.Chemoradiotherapy was added following progression(enlarged brain metastases)on maintenance treatment.Unfortunately,the brain lesions were highly refractory and progressed again after 15 mo,at which time next-generation sequencing(NGS)of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations.NGS revealed that the patient harbored a BRCA2 germline mutation,the EGFR exon 19 deletion mutation disappeared,and no additional targetable genetic variant was detected.Therefore,the patient received olaparib combined with gefitinib and recombinant human endostatin,with a rapid and long-lasting clinical response(PFS=13.5 mo).CONCLUSION This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment,suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.
文摘In late Dec.2019,a huge number of pneumonia cases caused by novel coronavirus were reported in China.2019-nCoV pandemic has influenced on millions of people's life across the world.This novel coronavirus was identified to be similar with MERS and SARS.Therefore,researchers and academicians across the world still trying to find out vaccines,new drug molecules against SARS-CoV-2.The principle point of this review article is to explain the activity of favipiravir in preventing COVID-19.In view of constrained data available in the literature,we specify that favipiravir treatment,among all other anti-viral drugs,accompanied by oxygen inhalation therapy,maintaining fluid and electrolyte balance,and nutritional support may be helpful in fighting COVID-19.Researches were done on already approved existing anti-viral drugs for treating ebola virus,influenza virus infection and many such anti-viral agents like favipiravir,ritonavir,remdesivir,ribavirin,oseltamivir shows promising results in preventing COVID-19 infection and their clinical trials are currently undergoing in order to discover proper treatment of COVID-19.Among the aforementioned drug candidates,a broad-spectrum RNA polymerase inhibitor favipiravir,which demonstrated a promising tolerance profile and anti-viral efficacy in patients having COVID-19 manifestations.
文摘The global burden of ovarian cancer is gradually increasing while patients still suffer from relatively limited treatment options.With recent advances in the decoding of the molecular landscape of ovarian cancer,more options in targeted strategy were offered and can therefore be tailored in different clinical settings for individual patient.Targeting of the abnormal angiogenesis process is the first significant clinical breakthrough which revolutionized the treatment of advanced ovarian cancer,followed by the advent of poly-(ADP)-ribose polymerase(PARP)inhibitors.These two strategies represented by bevacizumab and olaparib respectively underwent tests of numerous clinical trials.In recent years,immune checkpoint inhibitors(ICIs)have been incorporated into the blueprint of ovarian cancer treatment though the effectiveness still left much to be desired.Herein,we systematically outlined recent advances in targeted therapy for ovarian cancer and summarized the landmark clinical trials for each targeted therapy including angiogenesis inhibitors,PARP inhibitors and ICIs.
文摘Triple-negative breast cancer(TNBC),which accounts for approximately 15%of breast cancers(BCs)is characterized by a lack of expression of the hormone receptors(HRs)(estrogen receptor(ER)and progesterone receptor(PR)),and human epidermal growth factor receptor 2(HER2).TNBC reveals very aggressive behavior and often leads to poor prognosis.Unfortunately,standard chemotherapy(CHT)is related to low response rates and short progression-free survival(PFS)in patients with metastatic TNBC,creating an unmet need.However,recent recognition of different molecular subtypes and mutations within TNBC has allowed exploring some innovative targeted therapies,bringing new hope for women suffering from TNBC.Currently,some promising systemic treatment options in this area have been developed,including targeted therapies,such as poly(ADP-ribose)polymerase(PARP)inhibitors,immune checkpoint inhibitors,antibody-drug conjugates,and AKT inhibitors.The aim of this mini-review is to address these novel treatment modalities and highlight the main directions for further research and clinical practice in the advanced or metastatic forms of TNBC.This article presents poly(ADP-ribose)polymerase(PARP)inhibitors(e.g.,olaparib,talazoparib,and valaparib for treatment of BRCA-mutated,HER2-negative metastatic BC),immune checkpoint inhibitors(atezolizumab and pembrolizumab),an antibody-drug conjugate(ADC)(sacituzumab govitecan),and AKT inhibitors(ipatasertib and capivasertib).A brief outline of the main clinical trials leading to the approval of these new medications has been provided.Moreover,this overview discusses the efficacy and safety of these innovative treatment options,focusing on women with metastatic TNBC.In addition,this paper comments on some recent considerations,regarding avenues of delivering care and conduct clinical trials in patients with BC,during the COVID-19 pandemic.
文摘Background:Metastatic triple-negative breast cancer(mTNBC)is an aggressive histological subtype with poor prognosis.Several first-line treatments are currently available for mTNBC.This study conducted a network meta-analysis to compare these first-line regimens and to determine the regimen with the best efficacy.Methods:A systematic search of PubMed,EMBASE,the Cochrane Central Register of Controlled Bases,and mi-nutes of major conferences was performed.Progression-free survival(PFS),overall survival(OS),and objective response rate(ORR)were analyzed via network meta-analysis using the R software(R Core Team,Vienna,Austria).The efficacy of the treatment regimens was compared using hazard ratios and 95%confidence intervals.Results:A total of 29 randomized controlled trials involving 4607 patients were analyzed.The ranking was based on the surface under the cumulative ranking curve.Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR.For programmed death-ligand 1(PD-L1)and breast cancer susceptibility gene(BRCA)mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib was superior to docetaxel plus capecitabine.No significant difference was observed among the treatments in Os.Neutropenia,diarrhea,and fatigue were common serious adverse events.Conclusion:Cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC.For PD-L1 and BRCA mutation-positive tumors,atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option,Neutropenia,diarrhea,and fatigue are frequently occurring serious adverseevents.
文摘Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences in clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging mechanisms of resistance, and key clinical questions for future development.
基金supported by the National Key R&D Program of China(Grant No.2022YFC2409902)the National Natural Science Foundation of China(Grant No.82172876)+2 种基金the Beijing Nova Program of Science and Technology(Grant No.Z191100001119095)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(Grant No.2021-I2M-1-066)the Beijing Hope Run Special Fund of Cancer Foundation of China(Grant No.LC2019L04).
文摘Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency(HRD).HRD is found in a subgroup of cancer patients for several tumor types,and it has a clinical relevance to cancer prevention and therapies.Accumulating evidence has identified HRD as a biomarker for assessing the therapeutic response of tumor cells to poly(ADP-ribose)polymerase inhibitors and platinum-based chemotherapies.Nevertheless,the biology of HRD is complex,and its applications and the benefits of different HRD biomarker assays are controversial.This is primarily due to inconsistencies in HRD assessments and definitions(gene-level tests,genomic scars,mutational signatures,or a combination of these methods)and difficulties in assessing the contribution of each genomic event.Therefore,we aim to review the biological rationale and clinical evidence of HRD as a biomarker.This review provides a blueprint for the standardization and harmonization of HRD assessments.
文摘Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break(DSB)signaling.P53-binding protein 1(53BP1)plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining(NHEJ)-mediated DSB repair pathway that rejoins DSB ends.New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination(HR)signaling.This review focuses on the up-and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair,which in turn promotes the sensitivity of poly(ADP-ribose)polymerase inhibitor(PARPi)in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.
文摘Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies.Although initial response to therapy is observed,recurrence and ultimately chemoresistance result in overall therapeutic failure.This pattern has been evident with platinum therapy since the 1980s.Significant excitement surrounded the approval of poly(ADP-ribose)polymerase inhibition(PARPi)as a novel therapeutic option,especially with the advent of personalized medicine,but resistance has similarly developed to these treatments.Novel agents are constantly being sought,but if the obstacle of chemoresistance remains,the durability of responses will remain tenuous.Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured.Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.
