Source:Critical Reviews in Oncology/Hematology, Volume 121
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 23 Δεκεμβρίου 2017
Editorial Board
Source:Critical Reviews in Oncology/Hematology, Volume 121
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Mucins: Structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets
Source:Critical Reviews in Oncology/Hematology
Author(s): Suresh Sulekha Dhanisha, Chandrasekharan Guruayoorappan, Sudarsanan Drishya, Prathapan Abeesh
Mucins are the main structural components of mucus that create a selective protective barrier for epithelial surface and also execute wide range of other physiological functions. Mucins can be classified into two types, namely secreted mucins and membrane bounded mucins. Alterations in mucin expression or glycosylation and mislocalization has been seen in various types of pathological conditions such as cancers, inflammatory bowel disease and ocular disease, which highlight the importance of mucin in maintaining homeostasis. Hence mucins can be used as attractive target for therapeutic intervention. In this review, we discuss in detail about the structural diversity of mucins; their biosynthesis; its role in pathogenesis; regulation and as possible therapeutic targets.
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The ethical plausibility of the ‘Right To Try’ laws
Source:Critical Reviews in Oncology/Hematology
Author(s): D. Carrieri, F.A. Peccatori, G. Boniolo
'Right To Try' (RTT) laws originated in the USA to allow terminally ill patients to request access to early stage experimental medical products directly from the producer, removing the oversight and approval of the Food and Drug Administration. These laws have received significant media attention and almost equally unanimous criticism by the bioethics, clinical and scientific communities. They touch indeed on complex issues such as the conflict between individual and public interest, and the public understanding of medical research and its regulation. The increased awareness around RTT laws means that healthcare providers directly involved in the management of patients with life-threatening conditions such as cancer, infective, or neurologic conditions will deal more frequently with patients' requests of access to experimental medical products.This paper aims to assess the ethical plausibility of the RTT laws, and to suggest some possible ethical tools and considerations to address the main issues they touch.
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Non pharmacological interventions and non-fentanyl pharmacological treatments for breakthrough cancer pain: a systematic and critical review
Source:Critical Reviews in Oncology/Hematology
Author(s): Sebastiano Mercadante
Background: Oral opioids or other pharmacological or non-pharmacological interventions are often suggested in the management of breakthrough cancer pain (BTcP). The aim of this systematic and critical review was to analyse and critically comment the evidence of any non-fentanyl therapies proposed for BTcP.MethodsA systematic literature search was carried out to find studies providing clinical data on any treatment excluding fentanyl products.ResultsNo data exist about the use of oral opioids. Some information is available on parenteral morphine in a large sample of patients and episodes of BTcP. For other treatments, including methadone, nitrous oxide, anti-inflammatory drugs, samarium, and gabapentin the existing data, observational and obtained in a small number of patients do not provide useful information to be generalized. Only ketamine, a drug difficult to use for many physicians, particularly in determined setting, provided some evidence according a randomized controlled double-blind study.ConclusionsRecommendations suggesting the use of oral opioids or other pharmacological and non-pharmacologic interventions for BTcP, are not based on any, even minimal evidence. These treatments are worthwhile of further investigation, particularly in determined conditions that should fit the pharmacokinetics of oral opioids.
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Editorial Board
Source:Critical Reviews in Oncology/Hematology, Volume 121
http://ift.tt/2BKOkNh
Mucins: Structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets
Source:Critical Reviews in Oncology/Hematology
Author(s): Suresh Sulekha Dhanisha, Chandrasekharan Guruayoorappan, Sudarsanan Drishya, Prathapan Abeesh
Mucins are the main structural components of mucus that create a selective protective barrier for epithelial surface and also execute wide range of other physiological functions. Mucins can be classified into two types, namely secreted mucins and membrane bounded mucins. Alterations in mucin expression or glycosylation and mislocalization has been seen in various types of pathological conditions such as cancers, inflammatory bowel disease and ocular disease, which highlight the importance of mucin in maintaining homeostasis. Hence mucins can be used as attractive target for therapeutic intervention. In this review, we discuss in detail about the structural diversity of mucins; their biosynthesis; its role in pathogenesis; regulation and as possible therapeutic targets.
http://ift.tt/2zpjBj2
The ethical plausibility of the ‘Right To Try’ laws
Source:Critical Reviews in Oncology/Hematology
Author(s): D. Carrieri, F.A. Peccatori, G. Boniolo
'Right To Try' (RTT) laws originated in the USA to allow terminally ill patients to request access to early stage experimental medical products directly from the producer, removing the oversight and approval of the Food and Drug Administration. These laws have received significant media attention and almost equally unanimous criticism by the bioethics, clinical and scientific communities. They touch indeed on complex issues such as the conflict between individual and public interest, and the public understanding of medical research and its regulation. The increased awareness around RTT laws means that healthcare providers directly involved in the management of patients with life-threatening conditions such as cancer, infective, or neurologic conditions will deal more frequently with patients' requests of access to experimental medical products.This paper aims to assess the ethical plausibility of the RTT laws, and to suggest some possible ethical tools and considerations to address the main issues they touch.
http://ift.tt/2BHHkRw
Non pharmacological interventions and non-fentanyl pharmacological treatments for breakthrough cancer pain: a systematic and critical review
Source:Critical Reviews in Oncology/Hematology
Author(s): Sebastiano Mercadante
Background: Oral opioids or other pharmacological or non-pharmacological interventions are often suggested in the management of breakthrough cancer pain (BTcP). The aim of this systematic and critical review was to analyse and critically comment the evidence of any non-fentanyl therapies proposed for BTcP.MethodsA systematic literature search was carried out to find studies providing clinical data on any treatment excluding fentanyl products.ResultsNo data exist about the use of oral opioids. Some information is available on parenteral morphine in a large sample of patients and episodes of BTcP. For other treatments, including methadone, nitrous oxide, anti-inflammatory drugs, samarium, and gabapentin the existing data, observational and obtained in a small number of patients do not provide useful information to be generalized. Only ketamine, a drug difficult to use for many physicians, particularly in determined setting, provided some evidence according a randomized controlled double-blind study.ConclusionsRecommendations suggesting the use of oral opioids or other pharmacological and non-pharmacologic interventions for BTcP, are not based on any, even minimal evidence. These treatments are worthwhile of further investigation, particularly in determined conditions that should fit the pharmacokinetics of oral opioids.
http://ift.tt/2znYBcg
MRI evaluation of sacral chordoma treated with carbon ion radiotherapy alone
To compare RECIST 1.1 with volume modifications in patients with sacral chordoma not suitable for surgery treated with carbon ions radiotherapy (CIRT) alone. To evaluate patients pain before and after CIRT. To detect if baseline Apparent Diffusion Coefficient values (ADC) from Diffusion Weighted sequences could predict response to treatment.
http://ift.tt/2zmQm04
Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer
Abstract
Purpose
Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer.
Methods
Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline- and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars-Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of ≥ 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index.
Results
HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non-deficient patients (OR 13.06, CI 1.52–11.241, p = 0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65–160.41, p = 0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation > 99%).
Conclusions
HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents.
http://ift.tt/2kMoxde
Pulmonary tumor thrombotic microangiopathy successfully treated with corticosteroids: a case report
Pulmonary tumor thrombotic microangiopathy is a special type of tumor thromboembolism. We report the case of a patient who developed pulmonary tumor thrombotic microangiopathy with alveolar hemorrhage. Almost ...
http://ift.tt/2zlOF2N
No significant impact of response to prior androgen receptor-axis-targeted agents on the efficacy of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer
Abstract
Background
To investigate whether the response to an androgen receptor-axis-targeted (ARAT) agent is associated with the efficacy of subsequent docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients.
Methods
This study included 114 consecutive mCRPC patients, comprising 54 and 60 patients who progressed with abiraterone acetate (AA) and enzalutamide (Enz), respectively, before the introduction of docetaxel. The impact of the response to either ARAT agent on the activity of docetaxel was assessed.
Results
Following ARAT therapy, a prostate-specific antigen (PSA) response was observed in 73 of the 114 patients, of whom 33 and 40 received AA and Enz, respectively. In the 114 patients, PSA response to docetaxel was achieved in 48 (42.1%) patients, and median PSA progression-free survival (PFS) and overall survival (OS) with docetaxel were 7.2 and 17.5 months, respectively. No significant difference was noted in PSA response rate, PSA PFS or OS with docetaxel between responders and non-responders to a prior ARAT agent in the overall 114 patients, 54 receiving AA and 60 receiving Enz. Despite the absence of a significant impact of the response to a prior ARAT agent on PSA PFS or OS by univariate analysis, independent prognostic predictors were identified by multivariate analysis, as performance status (PS) for PSA PFS, and PS and visceral metastasis for OS.
Conclusions
Disease control by docetaxel may not be affected by the response to a prior ARAT agent. Therefore, a prior response to an ARAT agent should not influence the decision on the subsequent introduction of docetaxel for mCRPC patients.
http://ift.tt/2BXk26T
No significant impact of response to prior androgen receptor-axis-targeted agents on the efficacy of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer
Abstract
Background
To investigate whether the response to an androgen receptor-axis-targeted (ARAT) agent is associated with the efficacy of subsequent docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients.
Methods
This study included 114 consecutive mCRPC patients, comprising 54 and 60 patients who progressed with abiraterone acetate (AA) and enzalutamide (Enz), respectively, before the introduction of docetaxel. The impact of the response to either ARAT agent on the activity of docetaxel was assessed.
Results
Following ARAT therapy, a prostate-specific antigen (PSA) response was observed in 73 of the 114 patients, of whom 33 and 40 received AA and Enz, respectively. In the 114 patients, PSA response to docetaxel was achieved in 48 (42.1%) patients, and median PSA progression-free survival (PFS) and overall survival (OS) with docetaxel were 7.2 and 17.5 months, respectively. No significant difference was noted in PSA response rate, PSA PFS or OS with docetaxel between responders and non-responders to a prior ARAT agent in the overall 114 patients, 54 receiving AA and 60 receiving Enz. Despite the absence of a significant impact of the response to a prior ARAT agent on PSA PFS or OS by univariate analysis, independent prognostic predictors were identified by multivariate analysis, as performance status (PS) for PSA PFS, and PS and visceral metastasis for OS.
Conclusions
Disease control by docetaxel may not be affected by the response to a prior ARAT agent. Therefore, a prior response to an ARAT agent should not influence the decision on the subsequent introduction of docetaxel for mCRPC patients.
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Genome profile in a extremely rare case of pulmonary sclerosing pneumocytoma presenting with diffusely-scattered nodules in the right lung
.
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Some chemotherapeutics-treated colon cancer cells display a specific phenotype being a combination of stem-like and senescent cell features
.
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Lymphatic vessel involvement is predictive for lymph node metastasis and an important prognostic factor in endometrial cancer
Abstract
Background
Lymphovascular space involvement is reported to be an important risk factor in endometrial cancer. This study was conducted to evaluate the separate prognostic effects of lymphatic invasion and venous invasion on the outcomes of patients with endometrial cancer.
Methods
From 2006 to 2013, 189 histologically confirmed endometrial cancer patients were examined. To study the venous invasion (v) of the endometrial cancer, Victoria blue–H&E staining—which positively stains the elastic fibers of vessels—was performed. Immunohistochemical staining with D2-40 was used to study the lymphatic invasion (ly) of the endometrial cancer.
Results
The median age of the patients was 57 (range 25–84) years. ly(+) and/or v(+) patients were significantly more likely to present an advanced cancer stage, G3 tumor, and deep myometrial invasion than ly(−)/v(−) patients. The incidence of lymph node metastasis was high in ly(+) patients, and that of ovarian metastasis was high in v(+) patients. Lymphatic vessel invasion was significantly correlated with regional lymph node metastasis. We found a significantly higher incidence of distant metastasis in ly(+) patients. Most recurrences in ly(+)/v(−) patients occurred in lymph nodes, while those in ly(+)/v(+) patients occurred mainly at distant organs. Finally, the prognosis was significantly poorer for ly(+) patients, in whom lymphatic invasion was an independent prognostic factor along with distant metastasis.
Conclusions
Our study suggests that by separately evaluating lymphatic invasion and blood vessel invasion in endometrial cancer cases, useful information for predicting lymph node metastasis and recurrence sites as well as prognostic information can be obtained.
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Lymphatic vessel involvement is predictive for lymph node metastasis and an important prognostic factor in endometrial cancer
Abstract
Background
Lymphovascular space involvement is reported to be an important risk factor in endometrial cancer. This study was conducted to evaluate the separate prognostic effects of lymphatic invasion and venous invasion on the outcomes of patients with endometrial cancer.
Methods
From 2006 to 2013, 189 histologically confirmed endometrial cancer patients were examined. To study the venous invasion (v) of the endometrial cancer, Victoria blue–H&E staining—which positively stains the elastic fibers of vessels—was performed. Immunohistochemical staining with D2-40 was used to study the lymphatic invasion (ly) of the endometrial cancer.
Results
The median age of the patients was 57 (range 25–84) years. ly(+) and/or v(+) patients were significantly more likely to present an advanced cancer stage, G3 tumor, and deep myometrial invasion than ly(−)/v(−) patients. The incidence of lymph node metastasis was high in ly(+) patients, and that of ovarian metastasis was high in v(+) patients. Lymphatic vessel invasion was significantly correlated with regional lymph node metastasis. We found a significantly higher incidence of distant metastasis in ly(+) patients. Most recurrences in ly(+)/v(−) patients occurred in lymph nodes, while those in ly(+)/v(+) patients occurred mainly at distant organs. Finally, the prognosis was significantly poorer for ly(+) patients, in whom lymphatic invasion was an independent prognostic factor along with distant metastasis.
Conclusions
Our study suggests that by separately evaluating lymphatic invasion and blood vessel invasion in endometrial cancer cases, useful information for predicting lymph node metastasis and recurrence sites as well as prognostic information can be obtained.
http://ift.tt/2zjttKS
Correction to: Cerebrovascular CO 2 reactivity during isoflurane-nitrous oxide anesthesia in patients with chronic renal failure
Abstract
In the original publication of the article, the first sentence was published incorrectly under the section "Patients and preoperative assessment". The correct sentence should read as, "The Yamaguchi University Graduate School of Medicine Ethics Committee for Human Study approved the study protocol (18th August 2004: H16-71)".
http://ift.tt/2D2KtYj
Cancers, Vol. 10, Pages 3: Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells
Cancers, Vol. 10, Pages 3: Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells
Cancers doi: 10.3390/cancers10010003
Authors: Yoshiaki Sunami Artur Rebelo Jörg Kleeff
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.
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Cancers, Vol. 10, Pages 3: Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells
Cancers, Vol. 10, Pages 3: Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells
Cancers doi: 10.3390/cancers10010003
Authors: Yoshiaki Sunami Artur Rebelo Jörg Kleeff
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.
http://ift.tt/2BpodqY
CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials
Background
Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two Phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods
Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg once daily (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results
Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% (27/50; 95% confidence interval [CI] 39, 68), and 92% (46/50; 95% CI 81, 98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS DoR (22% maturity) was not reached (range: 1–15 months); at 9 months, 75% (95% CI 53, 88) of patients were estimated to remain in response. Median follow up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions
Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that previously reported. ClinicalTrials.gov number
NCT01802632; NCT02094261from Cancer via ola Kala on Inoreader http://ift.tt/2phVdA5
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Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with doxorubicin-based adjuvant chemotherapy (SWOG S9313)
Abstract
Background
Homologous recombination deficiency (HRD) causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313. Patients and Methods
425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing and BRCA1 PM, were performed on DNA isolated from FFPE tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation and/or a pre-defined HRD score ≥ 42. Markers were tested for prognostic value on DFS and OS using Cox regression models adjusted for treatment assignment and nodal status. Results
HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD-positive (27% with tBRCA mutation, 40% tBRCA negative but HRD score ≥42). HRD-positive status was associated with a better DFS (HR = 0.72; 95% CI 0.51– 1.00; p=0.049) and non-significant trend towards better OS (HR = 0.71; 95% CI 0.48– 1.03; p=0.073). High HRD score (≥42) in tBRCA-negative patients (n=274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; p=0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; p=0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD, but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; p=0.25). Conclusions
HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC based chemotherapy and should be evaluated further in prospective studies. Clinical Trials Number
Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment)from Cancer via ola Kala on Inoreader http://ift.tt/2DBgLdK
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Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient
anti-PD-1liver transplantation
from Cancer via ola Kala on Inoreader http://ift.tt/2phVe77
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from Cancer via ola Kala on Inoreader http://ift.tt/2phVe77
via IFTTT
Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with doxorubicin-based adjuvant chemotherapy (SWOG S9313)
Abstract
Background
Homologous recombination deficiency (HRD) causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313. Patients and Methods
425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing and BRCA1 PM, were performed on DNA isolated from FFPE tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation and/or a pre-defined HRD score ≥ 42. Markers were tested for prognostic value on DFS and OS using Cox regression models adjusted for treatment assignment and nodal status. Results
HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD-positive (27% with tBRCA mutation, 40% tBRCA negative but HRD score ≥42). HRD-positive status was associated with a better DFS (HR = 0.72; 95% CI 0.51– 1.00; p=0.049) and non-significant trend towards better OS (HR = 0.71; 95% CI 0.48– 1.03; p=0.073). High HRD score (≥42) in tBRCA-negative patients (n=274) was also associated with better DFS (HR = 0.64; 95% CI 0.43-0.94; p=0.023) and OS (HR = 0.65; 95% CI 0.42-1.00; p=0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD, but did not reach statistical significance (HR = 0.79; 95% CI 0.54-1.17; p=0.25). Conclusions
HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC based chemotherapy and should be evaluated further in prospective studies. Clinical Trials Number
Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment)http://ift.tt/2DBgLdK
Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient
anti-PD-1liver transplantation
http://ift.tt/2phVe77
http://ift.tt/2phVe77
CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two Phase II trials
Background
Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two Phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods
Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg once daily (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS). Results
Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% (27/50; 95% confidence interval [CI] 39, 68), and 92% (46/50; 95% CI 81, 98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS DoR (22% maturity) was not reached (range: 1–15 months); at 9 months, 75% (95% CI 53, 88) of patients were estimated to remain in response. Median follow up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions
Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that previously reported. ClinicalTrials.gov number
NCT01802632; NCT02094261http://ift.tt/2phVdA5
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