AbstractBackground.Individuals with serious mental illness (SMI) experience increased cancer mortality due to inequities in cancer treatment. Psychiatric care at cancer diagnosis may improve care delivery, yet models for integrating psychiatry and cancer care are lacking. We assessed the feasibility and acceptability of a person‐centered collaborative care trial for SMI and cancer.Subjects, Materials, and Methods.We developed the Bridge intervention for patients with SMI (schizophrenia, bipolar disorder, and severe major depression) and cancer. Bridge includes proactive identification of SMI, person‐centered care from a psychiatrist and case manager, and collaboration with oncology. We conducted a 12‐week, single‐group trial in patients with SMI and a new breast, gastrointestinal, lung, or head/neck cancer. We assessed the feasibility of patient identification, enrollment and study completion; evaluated acceptability and perceived benefit with exit interviews with patients, caregivers, and oncology clinicians; and examined change in psychiatric symptoms with the Brief Psychiatric Rating Scale (BPRS).Results.From November 2015 to April 2016, 30/33 eligible patients (90.9%) enrolled, and 25/29 (86.2%) completed assessments at all timepoints, meeting feasibility criteria. Of 24 patients, 23 (95.8%) found meeting with the psychiatrist helpful; 16/19 caregivers (84.2%) shared that Bridge addressed key caregiving challenges. Oncology clinicians evaluated Bridge as “very” or “most” useful for 94.3% of patients. Exit interviews with all participant groups suggested that Bridge fostered patient‐clinician trust, increased access to psychiatric treatment, and enabled patients to initiate and complete cancer treatment. Psychiatric symptoms on the BPRS improved from baseline to 12 weeks.Conclusion.Bridge is a feasible and acceptable care delivery model for patients with SMI, their caregivers, and oncology clinicians. Randomized trials are warranted to assess the efficacy of improving cancer outcomes in this underserved population.Implications for Practice.Serious mental illness affects 13 million U.S. adults who experience increased cancer mortality. To improve outcomes, new models of integrated oncology and mental health care are urgently needed. This study found that it was feasible to identify, enroll, and retain patients with serious mental illness and a new cancer in a trial of integrated mental health and cancer care (Bridge). Patients, caregivers, and oncologists reported that Bridge facilitated the initiation and completion of cancer care. Randomized trials are warranted to investigate the impact on cancer outcomes. Trial procedures may inform consent, engagement, and trial retention for patients with mental illness.
AbstractBackground.NUT carcinoma is a rare aggressive disease caused by BRD4/3‐NUT fusion, and C‐MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC‐targeting agents against patient‐derived NUT carcinoma cell lines.Materials and Methods.Thirteen patients with NUT carcinoma were evaluated for p53, C‐MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD‐L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU‐2972‐1, SNU‐3178S, HCC2429, and Ty‐82) were determined using MYC‐targeting agents, including bromodomain and extraterminal (BET) inhibitors (I‐BET, OTX‐015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC‐907).Results.Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3–23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long‐term survivor (>27 months). Although expressions of C‐MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD‐L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC‐907, was most potent against NUT carcinoma cells, with an IC50 of 5.5–9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4–1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7–8.2 nmol/L), also showed remarkable efficacies.Conclusion.East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC‐907 might be promising in NUT carcinoma treatment.Implications for Practice.NUT carcinoma (NC) is a disease caused by BRD‐NUT fusion leading to C‐MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC‐targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC‐targeting agents, including BET and HDAC inhibitors, CUDC‐907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC‐907 might be promising in NC treatment.
Hybrid Capture‐Based Genomic Profiling Identifies BRAF V600 and Non‐V600 Alterations in Melanoma Samples Negative by Prior Testing
AbstractBackground.BRAF and MEK inhibitors are approved for BRAF V600‐mutated advanced melanoma, with response rates of up to 70%. Responses to targeted therapies have also been observed for diverse non‐V600 BRAF alterations. Thus, sensitive, accurate, and broad detection of BRAF alterations is critical to match patients with available targeted therapies.Materials and Methods.Pathology reports were reviewed for 385 consecutive melanoma cases with BRAF mutations or rearrangements identified using a hybrid capture‐based next‐generation sequencing comprehensive genomic profiling (CGP) assay during the course of clinical care.Results.Records of prior BRAF molecular testing were available for 79 (21%) cases. Of cases with BRAF V600 mutations, 11/57 (19%) with available data were negative by prior BRAF testing. Prior negative BRAF results were also identified in 16/20 (80%) cases with non‐V600 mutations, 2 of which harbored multiple BRAF alterations, and in 2/2 (100%) cases with activating BRAF fusions. Clinical outcomes for a subset of patients are presented.Conclusion.CGP identifies diverse activating BRAF alterations in a significant fraction of cases with prior negative testing. Given the proven clinical benefit of BRAF/MEK inhibitors in BRAF‐mutated melanoma, CGP should be considered for patients with metastatic melanoma, particularly if other testing is negative.Implications for Practice.Published guidelines for melanoma treatment recommend BRAF mutational analysis, but little guidance is provided as to selection criteria for testing methodologies, or as to clinical implications for non‐V600 alterations. This study found that hybrid capture‐based next‐generation sequencing can detect BRAF alterations in samples from a significant fraction of patients with advanced melanoma with prior negative BRAF results. This study highlights the need for oncologists and pathologists to be critically aware of coverage and sensitivity limitations of various assays, particularly regarding non‐V600E alterations, of which many are potentially targetable.
Randomized Trial of a Tailored Cognitive‐Behavioral Therapy Mobile Application for Anxiety in Patients with Incurable Cancer
AbstractBackground.The aim of this study was to test the efficacy of a tailored cognitive‐behavioral therapy (CBT) mobile application (app) to treat anxiety in patients with incurable cancer.Materials and Methods.Patients with incurable cancers (n = 145) who reported elevated anxiety symptoms at two cancer centers were randomized to receive either the CBT mobile app for anxiety or a mobile health education program (control) delivered via tablet computers, which patients self‐administered over 12 weeks. To assess anxiety, depression symptoms, and quality of life (QOL), we used the Hamilton Anxiety Rating Scale (HAM‐A, primary outcome), Clinical Global Impression Scale, Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire‐9, and Functional Assessment of Cancer Therapy‐General at baseline and 12 weeks. Analysis of covariance models were calculated to assess intervention effects on patient outcomes.Results.Patients (73.8% female; 91.0% white; mean age = 56.45 years, SD = 11.30) in both study groups reported improvements in anxiety, depression symptoms, and QOL from baseline to postassessment, with no significant differences in any outcome measure between groups. Secondary analyses showed that, among the subgroup of patients with severe baseline anxiety, those randomized to the CBT app had greater improvements on the HAM‐A (Mean Difference = 7.44, standard error [SE] = 3.35, p = .037) and HADS‐Anxiety Subscale (Mean Difference = 4.44, SE = 1.60, p = .010) compared with the control group.Conclusion.Both the tailored CBT app for anxiety and the health education program were associated with improvements in anxiety, mood, and QOL, but these outcomes did not differ between study groups. The CBT app was more beneficial than health education for patients with severe baseline anxiety.Implications for Practice.A cognitive‐behavioral therapy mobile application tailored to treat anxiety in patients with advanced cancer helps improve access to evidence‐based supportive care in a convenient, private, and timely manner.
Suspected Hereditary Cancer Syndromes in Young Patients: Heterogeneous Clinical and Genetic Presentation of Colorectal Cancers
AbstractColorectal cancer (CRC) is rare in young patients without a confirmed family history of cancer. Reports of an increased prevalence of POLD1/POLE mutations in young patients with colorectal cancer have raised awareness and support routine genetic testing for patients with early‐onset tumors. In cases of CRC without proven MMR‐germline mutation, molecular analyses are warranted to confirm or rule out other familial CRC syndromes. This article describes the cases of two young male patients, who presented with locally advanced and metastatic CRC, and reports the results of the germline mutational analyses done for both patients. These cases demonstrate the importance of special care and molecular diagnostic procedures for young patients with CRC.Key Points. Patients with colorectal cancer who are younger than 50 years at initial diagnosis (early onset) should routinely undergo genetic testing.Early‐ and very‐early‐onset patients (younger than 40 years) with absence of microsatellite instability should be considered for tumor mutation burden testing and/or DNA polymerase proofreading mutation.The mutational signature of HSP110 within mismatch repair deficiency‐related tumors may help to identify patients likely to benefit from 5‐fluorouracil‐based chemotherapy.Intensified, maintained, and specific surveillance may help to reduce secondary tumor progression.
AbstractWith the advent of next‐generation sequencing (NGS) and precision medicine, investigators have determined that tumors from different tissue sources that have the same types of genetic mutations will have a positive response to the same targeted therapy. This finding has prompted us to seek potential therapeutic targets for patients with carcinoma of unknown primary (CUP) using NGS technology. Here, we reported a case of a woman with CUP resistance to chemotherapy. We detected 450 cancer‐related gene alterations using three metastatic tumor specimens and found the presence of EML4 exon13 and ALK exon20 fusion. The tumor did respond to crizotinib, a first‐generation ALK inhibitor. When her tumor progressed, circulating tumor DNA detection revealed ALK L1196 M and G1269A mutation resistance to crizotinib, but she had a response to brigatinib. This case revealed that NGS technology used to detect the genetic alterations in patients with CUP might be a reliable method to find potential therapeutic targets, although the primary lesion could not always be confirmed.Key Points.This case exemplifies responsiveness to ALK inhibitor in carcinoma of unknown primary (CUP) with EML4‐ALK fusion.Next‐generation sequencing is an important diagnostic tool to find potential therapeutic targets in CUP.Liquid biopsy may be useful to provide critical information about resistance mechanisms in CUP to guide sequential treatment decision with targeted therapy.
Everolimus plus Exemestane for Hormone Receptor‐Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO‐2
AbstractBackground.The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]‐enriched and basal‐like) subtypes within advanced hormone receptor‐positive (HR+) breast cancer is currently unknown.Materials and Methods.This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO‐2 study; BOLERO‐2 randomized 724 patients with advanced HR+/HER2‐negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression‐free survival (PFS) were evaluated.Results.Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2‐enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal‐like (n = 37), and 1.9% basal‐like (n = 5); HER2‐enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p = .038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47–0.94; p = .020) and HER2‐enriched and non‐HER2‐enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07–2.19; p = .019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2‐enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26–0.90; p = .034); however, the association between HER2‐enriched tumors and everolimus benefit was nonsignificant (p = .433).Conclusion.The HER2‐enriched subtype was identified in a substantial proportion of advanced HR+/HER2‐negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2‐enriched tumors in the advanced HR+/HER2‐negative breast cancer setting.Implications for Practice.Using 261 tumor samples from the BOLERO‐2 phase III clinical trial, this study shows that a substantial proportion (20%–30%) of hormone receptor‐positive (HR+)/human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2‐negative breast cancer.
Aromatase Inhibitors and Newly Developed Nonalcoholic Fatty Liver Disease in Postmenopausal Patients with Early Breast Cancer: A Propensity Score‐Matched Cohort Study
AbstractBackground.Unlike tamoxifen, the relationship between aromatase inhibitor use in postmenopausal patients with breast cancer and nonalcoholic fatty liver disease (NAFLD) has not been delineated.Materials and Methods.A retrospective analysis of 253 patients with early breast cancer without baseline NAFLD and treated with nonsteroidal aromatase inhibitors was performed. Among them, 220 patients were matched for sex, age, and menstruation status with healthy patients, and the prevalence of NAFLD was compared. NAFLD was determined by hepatic steatosis index in the absence of other known liver diseases. The presence of significant liver fibrosis in patients with NAFLD was determined noninvasively by AST‐platelet ratio index, FIB‐4 score, and NAFLD fibrosis score (NFS).Results.Postmenopausal patients with breast cancer undergoing treatment with aromatase inhibitors had higher prevalence of NAFLD independent of body mass index (BMI) and underlying diabetes mellitus (DM). Although the aromatase inhibitor group showed higher fibrotic burden by NFS, independent of BMI and DM, the proportion of advanced fibrosis did not show statistically significant differences between AI‐treated patients and the healthy patients. Those with abnormal baseline fasting glucose levels are suggested to have increased risk of NAFLD development after aromatase inhibitor treatment. In addition, patients with NAFLD developed after aromatase inhibitor use had significantly lower disease‐free survival than those without NAFLD, although there was no significant difference in overall survival.Conclusion.Results of this study suggest that inhibition of estrogen synthesis in postmenopausal women undergoing treatment with aromatase inhibitors could increase the risk of NAFLD, which might have some influence on the prognosis of patients with breast cancer.Implications for Practice.Unlike tamoxifen, the role of aromatase inhibitor treatment use in postmenopausal patients with breast cancer in development of fatty liver is not well known. In this propensity‐matched cohort study, postmenopausal patients with breast cancer treated with aromatase inhibitors had increased risk of nonalcoholic fatty liver disease compared with healthy women after menopause, independent of obesity and diabetes mellitus. The results show possible adverse influence of the newly developed fatty liver on breast cancer disease‐free survival and suggest a necessity for further validation. Fatty liver may need to be considered as an adverse event for aromatase inhibitor treatment.
AbstractLessons Learned.The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5‐fluorouracil (5‐FU) in metastatic colorectal cancer (mCRC) after long exposure to 5‐FU.S‐1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third‐ or later‐line therapy in mCRC.Background.5‐fluorouracil (5‐FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5‐FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5‐FU. To evaluate the efficacy and safety of S‐1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one‐center, single‐arm, prospective phase II trial was conducted.Methods.Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S‐1 (80–120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m2 on day 1 every 3 weeks). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), and toxicity.Results.In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention‐to‐treat population (n = 46), the ORR was 13.0% and disease control rate was 54.3%. Median PFS and median OS were 107 days (95% confidence interval [CI], 96.3–117.7) and 373 days (95% CI, 226.2–519.8), respectively. Most of the adverse effects were mild to moderate.Conclusion.S‐1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third‐ or later‐line therapy in mCRC.
Phase II Study of the Triple Combination Chemotherapy of SOXIRI (S‐1/Oxaliplatin/Irinotecan) in Patients with Unresectable Pancreatic Ductal Adenocarcinoma
AbstractLessons Learned. The triple combination chemotherapy of SOXIRI (S‐1/oxaliplatin/irinotecan) in patients with unresectable pancreatic ductal adenocarcinoma was an effective treatment that appeared to be better tolerated than the widely used FOLFIRINOX regimen.SOXIRI regimen may provide an alternative approach for advanced pancreatic cancer.Background.In our previous phase I study, we determined the recommended dose of a biweekly S‐1, oxaliplatin, and irinotecan (SOXIRI) regimen in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). This phase II study was conducted to assess the safety and clinical efficacy in patients with unresectable PDAC.Methods.Patients with previously untreated metastatic and locally advanced PDAC were enrolled. The primary endpoint was response rate (RR). Secondary endpoints were adverse events (AEs), progression‐free survival (PFS), and overall survival (OS). Patients received 80 mg/m2 of S‐1 twice a day for 2 weeks in alternate‐day administration, 150 mg/m2 of irinotecan on day 1, and 85 mg/m2 of oxaliplatin on day 1 of a 2‐week cycle.Results.Thirty‐five enrolled patients received a median of six (range: 2–15) treatment cycles. The RR was 22.8% (95% confidence interval [CI]: 10.4–40.1); median OS, 17.7 months (95% CI: 9.8–22.0); and median PFS, 7.4 months (95% CI: 4.2–8.4). Furthermore, the median OS in patients with distant metastasis was 10.1 months, whereas that in patients with locally advanced PDAC was 22.6 months. Major grade 3 or 4 toxicity included neutropenia (54%), anemia (17%), febrile neutropenia (11%), anorexia (9%), diarrhea (9%), and nausea (9%). There were no treatment‐related deaths.Conclusion.SOXIRI is considered a promising and well‐tolerated regimen in patients with unresectable PDAC.
A Phase II Randomized Trial of Panitumumab, Erlotinib, and Gemcitabine Versus Erlotinib and Gemcitabine in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma: North Central Cancer Treatment Group Trial N064B (Alliance)
AbstractLessons Learned. Dual epidermal growth factor receptor (EGFR)‐directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR‐directed therapy.The dual EGFR‐directed therapy resulted in increased toxicity.Background.Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab.Methods.Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28‐day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28‐day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression‐free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one‐sided log‐rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two‐sided.Results.A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530–1.260; p = .1792). The progression‐free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555–1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018).Conclusion.Dual EGFR‐directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR‐directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single‐agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.
Diagnosis and Treatment Monitoring of a Patient with Gastrointestinal Stromal Tumor by Next‐Generation Sequencing and Droplet Digital Polymerase Chain Reaction Assay of a PDGFRA Mutation in Plasma‐Derived Cell‐Free Tumor DNA
AbstractIn patients with a suspected malignancy, standard‐of care management currently includes histopathologic examination and analysis of tumor‐specific molecular abnormalities. Herein, we present a 77‐year‐old patient with an abdominal mass suspected to be a gastrointestinal stromal tumor (GIST) but without the possibility to collect a tumor biopsy. Cell‐free DNA extracted from a blood sample was analyzed for the presence of mutations in GIST‐specific genes using next generation sequencing. Furthermore, liquid biopsies were used to monitor the levels of mutant DNA copies during treatment with a tumor‐specific mutation droplet digital PCR assay that correlated with the clinical and radiological response. Blood‐based testing is a good alternative for biopsy‐based testing. However, it should only be applied when biopsies are not available or possible to obtain because overall, in only 50%–85% of the cell‐free plasma samples is the known tumor mutation detected.
AbstractBackground.There has been a significant increase in the use of immunotherapy and cannabis recently, two modalities that have immunomodulatory effects and may have possible interaction. We evaluated the influence of cannabis use during immunotherapy treatment on response rate (RR), progression‐free survival (PFS), and overall survival (OS).Subjects, Materials, and Methods.In this retrospective, observational study, data were collected from the files of patients treated with nivolumab in the years 2015–2016 at our hospital, and cannabis from six cannabis‐supplying companies. Included were 140 patients (89 nivolumab alone, 51 nivolumab plus cannabis) with advanced melanoma, non‐small cell lung cancer, and renal clear cell carcinoma. The groups were homogenous regarding demographic and disease characteristics. A comparison between the two arms was made.Results.In a multivariate model, cannabis was the only significant factor that reduced RR to immunotherapy (37.5% RR in nivolumab alone compared with 15.9% in the nivolumab‐cannabis group (p = .016, odds ratio = 3.13, 95% confidence interval 1.24–8.1). Cannabis use was not a significant factor for PFS or OS. Factors affecting PFS and OS were smoking (adjusted hazard ratio [HR] = 2.41 and 2.41, respectively (and brain metastases (adjusted HR = 2.04 and 2.83, respectively). Low performance status (adjusted HR = 2.83) affected OS alone. Tetrahydrocannabinol and cannabidiol percentages did not affect RR in any group (p = .393 and .116, respectively).Conclusion.In this retrospective analysis, the use of cannabis during immunotherapy treatment decreased RR, without affecting PFS or OS and without relation to cannabis composition. Considering the limitations of the study, further prospective clinical study is needed to investigate possible interaction.Implications for Practice.Although the data are retrospective and a relation to cannabis composition was not detected, this information can be critical for cannabis users and indicates that caution is required when starting immunotherapy.
Effects of Oral Morphine on Dyspnea in Patients with Cancer: Response Rate, Predictive Factors, and Clinically Meaningful Change (CJLSG1101)
AbstractBackground.Although the efficacy of parenteral morphine for alleviating dyspnea has been previously demonstrated in several studies, little is known regarding the efficacy of oral morphine for dyspnea among patients with cancer, including its response rate and predictive factors of effectiveness. Therefore, the aim of this study was to clarify the effectiveness of oral morphine on dyspnea in patients with cancer and elucidate the predictive factors of its effectiveness.Subjects, Materials, and Methods.In this multicenter prospective observational study, we investigated the change in dyspnea intensity in patients with cancer before and after the administration of oral morphine by using a visual analog scale (VAS). We also administered a self‐assessment questionnaire to determine whether the patients believed oral morphine was effective.Results.Eighty patients were enrolled in the study, and 71 of these patients were eligible. The least square mean of the VAS scores for dyspnea intensity was 53.5 at baseline, which decreased significantly to 44.7, 40.8, and 35.0 at 30, 60, and 120 minutes after morphine administration, respectively. Fifty‐four patients (76.1%) reported that oral morphine was effective on the self‐assessment questionnaire. Among the background factors, a high score for “sense of discomfort” on the Cancer Dyspnea Scale (CDS) and a smoking history of fewer pack‐years were associated with greater effectiveness.Conclusion.Oral morphine was effective and feasible for treating cancer‐related dyspnea. A higher score for “sense of discomfort” on the CDS and a smaller cumulative amount of smoking may be predictive factors of the effectiveness of oral morphine.Implications for Practice.This study demonstrated that oral morphine was effective in alleviating cancer‐related dyspnea due to multiple factors including primary lung lesions, airway narrowing, and pleural effusion. Approximately 76% of patients reported that oral morphine was effective. A higher score for “sense of discomfort” on the Cancer Dyspnea Scale and a lower cumulative amount of smoking may be predictive factors for the effectiveness of oral morphine. Interestingly, respiratory rates in patients who reported the morphine to be effective decreased significantly after oral morphine administration, unlike the respiratory rates in “morphine‐ineffective” patients.
Genomic Features for Therapeutic Insights of Chemotherapy‐Resistant, Primary Mediastinal Nonseminomatous Germ Cell Tumors and Comparison with Gonadal Counterpart
AbstractPrimary mediastinal nonseminomatous germ cell tumors (PMNSGCT) frequently become refractory to chemotherapy, and no effective salvage therapy exists. We performed genomic profiling on a series of 44 PMNSGCT and compared the results with those from chemorefractory, metastatic pure seminomatous (Sem, n = 22) and nonseminomatous (NS, n = 86) testicular germ cell tumors. Archival tissues were sequenced by a hybrid capture‐based technology (FoundationONE; Foundation Medicine, Inc., Cambridge, MA). Microsatellite instability (MSI) and tumor mutational burden (TMB, mutations [mut]/Mb) were determined.Statistically significant differences in genomic alterations (GA) of PMNSGCT versus NS included higher TP53 pathway GA (p < .0001), PIK3CA pathway GA (p < .0001), and lower cell‐cycle pathway GA (p = .0004). There were no MSI‐high PMNSGCT cases. Mean TMB was similar between the groups, but there were more ≥10 mut/Mb in the PMNSGCT group versus NS (11.4% vs. 4.6%).The GA identified in PMNSGCT were similar to the findings from NS, with differential opportunities for targeted therapies and immunotherapies. Further study of precision treatments appears warranted.
Eribulin Mesylate as Third or Subsequent Line Chemotherapy for Elderly Patients with Locally Recurrent or Metastatic Breast Cancer: A Multicentric Observational Study of GIOGer (Italian Group of Geriatric Oncology)‐ERIBE
AbstractBackground.Metastatic breast cancer (MBC) is highly prevalent in middle‐aged or elderly patients. Eribulin is a nontaxane microtubule inhibitor, approved for the treatment of pretreated MBC. This multicentric study (sponsored by GIOGer, Italian Group for Geriatric Oncology) was designed to assess the efficacy and tolerability of eribulin, according to parameters usually used in geriatric oncology.Subjects, Materials, and Methods.An observational study was conducted on 50 consecutive elderly patients with MBC. The primary endpoint was to evaluate the change in items score of comprehensive geriatric assessment (CGA) and health‐related quality of life (HRQL). Italian versions of the CGA and HRQL questionnaires were administered at baseline, before the third and fifth cycles, and then every three cycles until treatment discontinuation. Secondary endpoints were efficacy and safety.Results.Overall, both EQ‐5D scores and EQ‐5D‐3 L visual analogic scale did not significantly change from baseline; the percentage of subjects without problems doing usual activities tended to decrease during treatment (p for linear trend .018), and the percentage of patients with minor problems performing usual activities tended to increase (p for linear trend.012). Among CGA items, Instrumental Activities of Daily Living tended to decrease during treatment and Geriatric Depression Scale tended to increase. After 12 months follow‐up, 24 patients (out of 47) showed clinical benefits; median progression‐free survival was 4.49 months (2.10–10.33) and median OS was 7.31 months (3.70–14.03). The treatment was associated with mild toxicity.Conclusion.Eribulin treatment preserved quality of life and geriatric parameters included in the CGA, except for instrumental functioning and geriatric depression, in elderly patients with MBC.Implications for Practice.A collaboration between oncologist and geriatric specialists is essential in the management of patients with metastatic breast cancer, who are frequently elderly or frail. The assessment of geriatric parameters in the decision‐making process can contribute to direct toward the most appropriate therapeutic plan and preserve the quality of life of patients. Eribulin does not seem to affect quality of life or worsen the overall geriatric status; therefore, it can be considered a suitable option for elderly patients with metastatic breast cancer.
Osimertinib in Elderly Patients with Epidermal Growth Factor Receptor T790M‐Positive Non‐Small‐Cell Lung Cancer Who Progressed During Prior Treatment: A Phase II Trial
AbstractLessons Learned. Non‐small‐cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients.In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation‐positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population.Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted.Background.Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M‐positive non‐small‐cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect.Methods.This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation‐positive NSCLC.Results.A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%–72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1–82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug.Conclusion.Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.
Exploring Biomarkers of Phosphoinositide 3‐Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer
AbstractResistance to endocrine therapy (ET) is common in patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Consequently, new targeted treatment options are needed in the post‐ET setting, with validated biomarkers to inform treatment decisions. Hyperactivation of the phosphoinositide 3‐kinase (PI3K) signaling pathway is common in ABC and is implicated in resistance to ET. The most frequent mechanism of PI3K pathway activation is activating mutations or amplification of PIK3CA, which encodes the α‐isoform of the catalytic subunit of PI3K. Combining buparlisib, a pan‐PI3K‐targeted agent, with ET demonstrated modest clinical benefits in patients with aromatase inhibitor‐resistant, HR+, human epidermal growth receptor 2 negative (HER2−) ABC in two phase III trials. Importantly, greater efficacy gains were observed in individuals with PIK3CA‐mutated disease versus PIK3CA‐wild‐type tumors. Although the challenging safety profile did not support widespread use of this treatment combination, isoform‐selective PI3K inhibitors may improve tolerability. In early clinical trials, promising disease control benefits were demonstrated with the PI3K isoform‐selective inhibitors alpelisib and taselisib in patients with PIK3CA‐mutated HR+, HER2− ABC. Ongoing biomarker‐guided phase II/III studies may provide further opportunities to identify patients most likely to benefit from treatment with PI3K inhibitors and provide insight into optimizing the therapeutic index of PI3K inhibitors. Challenges facing the implementation of routine PIK3CA mutation testing must be addressed promptly so robust and reproducible genotyping can be obtained with liquid and tumor biopsies in a timely and cost‐effective manner.Implications for Practice.The development of phosphoinositide 3‐kinase (PI3K) inhibitors, especially those that selectively target isoforms, may be an effective strategy for overcoming endocrine therapy resistance in hormone receptor positive, human epidermal growth receptor 2 negative advanced breast cancer. Early‐phase studies have confirmed that patients with PIK3CA mutations respond best to PI3Kα‐isoform inhibition. Ongoing phase III trials will provide further data regarding the efficacy and safety of PI3K inhibitors in patients with different biomarker profiles.
Long‐Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome
AbstractBackground.Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome.Subjects, Materials, and Methods.Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long‐term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated.Results.Mean (median; range) duration of exposure and follow‐up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient‐years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4.Conclusion.Based on long‐term safety data, telotristat ethyl is well tolerated and has a favorable long‐term safety profile in patients with carcinoid syndrome.Implications for Practice.Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.
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