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PURPOSE: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 (NF1[S1] or GNA11/Q [S2]) altered tumors. METHODS: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.
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Melanoma , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibromatosis 1/inducido químicamente , Pirimidinonas/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Piridonas/uso terapéutico , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP/genéticaRESUMEN
PURPOSE: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3. PATIENTS AND METHODS: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles. RESULTS: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%). CONCLUSIONS: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification.
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Neoplasias de la Mama , Neutropenia , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Piperazinas , Piridinas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclina D1/genéticaRESUMEN
PURPOSE: Bone marrow biopsies (BMB) are performed before/after therapy to confirm complete response (CR) in patients with lymphoma on clinical trials. We sought to establish whether BMB add value in assessing response or predict progression-free survival (PFS) or overall survival (OS) outcomes in follicular lymphoma (FL) subjects in a large, multicenter, multitrial cohort. METHODS: Data were pooled from seven trials of 580 subjects with previously untreated FL through Alliance for Clinical Trials in Oncology (Alliance) and SWOG Cancer Research Network (SWOG) completing enrollment from 2008 to 2016. RESULTS: Only 5/580 (0.9%) had positive baseline BMB, CR on imaging, and subsequent positive BMB (P < .0001). Therefore, BMB were irrelevant to response in 99% of subjects. A sensitivity analysis of 385 FL subjects treated on an Eastern Cooperative Oncology Group study was included. In the Eastern Cooperative Oncology Group cohort, 5/385 (1.3%) had BMB that affected response assessment. Since some subjects do not undergo confirmatory BMB, we performed a landmark survival analysis from first radiologic CR with data from 580 subjects from Alliance and SWOG. Of subjects with CR on imaging (n = 187), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 47) versus those without repeat BMB (n = 140; PFS: adjusted hazard ratio, 1.10, 95% CI, 0.62 to 1.94, log-rank P = .686; OS: hazard ratio, 0.59, 95% CI, 0.23 to 1.53, log-rank P = .276). CONCLUSION: We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment.
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Linfoma Folicular , Estados Unidos , Humanos , Linfoma Folicular/tratamiento farmacológico , Médula Ósea/patología , National Cancer Institute (U.S.) , Análisis de Supervivencia , BiopsiaRESUMEN
BACKGROUND: Quantitative reports suggest that the assessment and management of chemotherapy-induced peripheral neuropathy (CIPN) in practice is suboptimal. OBJECTIVE: The purpose of this qualitative analysis was to explore clinician-related perspectives of CIPN assessment, management, and the use of a CIPN decision support tool. METHODS: Clinicians from the breast oncology, gastrointestinal oncology, or multiple myeloma disease centers at Dana-Farber Cancer Institute who interacted with a CIPN clinician decision support algorithm were eligible to participate in the semi-structured interviews. The interview guide included questions about CIPN assessment, management, and clinician-decision support tool use. All interviews were audio-recorded, transcribed, and analyzed using inductive content analysis. RESULTS: Of the 39 eligible clinicians, 15 agreed to be interviewed. Interviewed clinicians were mainly physicians (73.3) and White, non-Hispanic (93.3%). Main themes from the interviews included (1) CIPN management practice patterns (eg, endorsement of non-recommended management strategies or lack of standardization for chemotherapy dose reduction) and barriers (eg, insurance prior authorizations required for duloxetine prescription), (2) CIPN assessment practice patterns (eg, use of subjective instead of objective CIPN assessment approaches) and barriers (eg, difficult to interpret patients' CIPN report between visits), and (3) utilization of the clinician decision support tool (eg, all assessment tasks lead to same management options). CONCLUSIONS: There are several barriers to clinicians' use of evidence-based CIPN assessment and management strategies. IMPLICATIONS FOR PRACTICE: Future work should be focused on addressing barriers to duloxetine prescription, developing evidence-based CIPN assessment and management strategies, improving symptom monitoring, and facilitating referrals to existing supportive care services.
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Antineoplásicos , Mieloma Múltiple , Enfermedades del Sistema Nervioso Periférico , Humanos , Antineoplásicos/efectos adversos , Clorhidrato de Duloxetina/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/terapia , Oncología MédicaRESUMEN
OBJECTIVE: Greater perceived patient-centered communication (PCC) is associated with better health-related quality of life (HRQoL) in patients with ovarian cancer. Quantitative measures of PCC and HRQoL do little to explain this association. We interviewed patients with high and low ratings of PCC to understand how it is associated with HRQoL. METHODS: Explanatory sequential mixed methods study. Participants were English-speaking U.S. adults with ovarian cancer. We assessed PCC with the Patient-Centered Communication - Cancer (PCC-Ca)-36 (possible score range 1-5; higher scores represent greater patient-centeredness), and purposively sampled 14 participants with total scores in the top and bottom quartiles. Participants completed individual, semi-structured interviews about their communication experiences. Guided by the National Cancer Institute Framework for PCC in Cancer Care, we analyzed interview transcripts using directed content analysis. We integrated survey and interview findings in a joint display. RESULTS: Among 176 survey respondents, PCC-Ca-36 total scores ranged from 1.7 to 5.0. Participants with scores in the top quartile (4.8-5.0) perceived clinicians as proactive and attentive to psychosocial concerns. Those with scores in the bottom quartile (1.7-3.5) described not feeling known as an individual and receiving limited support for self-management. CONCLUSIONS: The association between PCC and QoL may be partially explained by differences in perceived support for psychosocial concerns and self-management. PCC may facilitate receipt of proactive, personalized care.
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Neoplasias Ováricas , Calidad de Vida , Adulto , Humanos , Femenino , Atención Dirigida al Paciente/métodos , Encuestas y Cuestionarios , Neoplasias Ováricas/terapia , ComunicaciónRESUMEN
BACKGROUND: Although treatment decisions for localized prostate cancer (LPC) are preference-sensitive, the extent to which individuals with LPC receive preference-concordant treatment is unclear. In a sample of individuals with LPC, the purpose of this study was to (a) assess concordance between the influence of potential adverse treatment outcomes and treatment choice; (b) determine whether receipt of a decision aid predicts higher odds of concordance; and (c) identify predictors of concordance from a set of participant characteristics and influential personal factors. METHODS: Participants reported the influence of potential adverse treatment outcomes and personal factors on treatment decisions at baseline. Preference-concordant treatment was defined as (a) any treatment if risk of adverse outcomes did not have a lot of influence, (b) active surveillance if risk of adverse outcomes had a lot of influence, or (c) radical prostatectomy or active surveillance if risk of adverse bowel outcomes had a lot of influence and risk of other adverse outcomes did not have a lot of influence. Data were analyzed using descriptive statistics and logistic regression. RESULTS: Of 224 participants, 137 (61%) pursued treatment concordant with preferences related to adverse treatment outcomes. Receipt of a decision aid did not predict higher odds of concordance. Low tumor risk and age ≥ 60 years predicted higher odds of concordance, while attributing a lot of influence to the impact of treatment on recreation predicted lower odds of concordance. CONCLUSIONS: Risk of potential adverse treatment outcomes may not be the foremost consideration of some patients with LPC. Assessment of the relative importance of patients' stated values and preferences is warranted in the setting of LPC treatment decision making. CLINICAL TRIAL REGISTRATION: NCT01844999 ( www. CLINICALTRIALS: gov ).
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Toma de Decisiones , Neoplasias de la Próstata , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Prostatectomía , Neoplasias de la Próstata/cirugía , Resultado del TratamientoRESUMEN
Central vascular access devices (CVADs) are often essential to the care of patients undergoing long-term cancer treatment. CVAD maintenance is an essential oncology nurse competency. Evidence-based practice (EBP) in flushing and locking help to prevent intraluminal occlusion, a common complication. Heparinized saline (HS) has been the standard locking solution for CVADs. However, research indicates no superiority of HS over normal saline (NS). The objectives of this EBP project were 1) to evaluate whether a significant difference in intraluminal occlusion was associated with the change from HS to NS use for locking CVADs in ambulatory oncology care, and 2) to evaluate the effects of peer nurse mentoring on nurses' and patients' perspectives about the practice change. Analysis of data revealed decreases in alteplase usage after transitioning to NS locking. Patient and nurse surveys indicated that peer nurse mentoring increased nurse and patient confidence and competence in making the practice transition.
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The objective of this study is to examine the association between neighborhood socioeconomic status (nSES) and baseline allostatic load (AL) and clinical trial endpoints in patients enrolled in the E1A11 therapeutic trial in multiple myeloma (MM). Study endpoints were symptom burden (pain, fatigue, and bother) at baseline and 5.5 months, non-completion of induction therapy, overall survival (OS) and progression-free survival (PFS). Multivariable logistic and Cox regression examined associations between nSES, AL and patient outcomes. A 1-unit increase in baseline AL was associated with greater odds of high fatigue at baseline (adjusted OR [95% CI] = 1.21 [1.08-1.36]) and a worse OS (adjusted hazard ratio, [95% CI] = 1.21 [1.06-1.37]). High nSES was associated with worse baseline bother (middle OR = 4.22 [1.11-16.09] and high 4.49 [1.16-17.43]) compared to low nSES. There was no association between AL or nSES and symptom burden at 5.5 months, non-completion of induction therapy or PFS. Additionally, there was no association between nSES and OS. AL may have utility as a predictive marker for OS among patients with MM and may allow individualization of treatment. Future studies should standardize and validate AL patients with MM.
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Alostasis , Mieloma Múltiple , Humanos , Mieloma Múltiple/epidemiología , Mieloma Múltiple/terapia , Modelos de Riesgos Proporcionales , Características de la Residencia , Clase SocialRESUMEN
RAS family members are the most frequently mutated oncogenes in human cancers. Although KRAS(G12C)-specific inhibitors show clinical activity in patients with cancer1-3, there are no direct inhibitors of NRAS, HRAS or non-G12C KRAS variants. Here we uncover the requirement of the silent KRASG60G mutation for cells to produce a functional KRAS(Q61K). In the absence of this G60G mutation in KRASQ61K, a cryptic splice donor site is formed, promoting alternative splicing and premature protein termination. A G60G silent mutation eliminates the splice donor site, yielding a functional KRAS(Q61K) variant. We detected a concordance of KRASQ61K and a G60G/A59A silent mutation in three independent pan-cancer cohorts. The region around RAS Q61 is enriched in exonic splicing enhancer (ESE) motifs and we designed mutant-specific oligonucleotides to interfere with ESE-mediated splicing, rendering the RAS(Q61) protein non-functional in a mutant-selective manner. The induction of aberrant splicing by antisense oligonucleotides demonstrated therapeutic effects in vitro and in vivo. By studying the splicing necessary for a functional KRAS(Q61K), we uncover a mutant-selective treatment strategy for RASQ61 cancer and expose a mutant-specific vulnerability, which could potentially be exploited for therapy in other genetic contexts.
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Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Mutación Silenciosa , Empalme Alternativo/genética , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/uso terapéutico , Oncogenes/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Sitios de Empalme de ARN/genéticaRESUMEN
BACKGROUND: The early identification of chemotherapy-induced peripheral neuropathy (CIPN) (e.g., numbness or tingling in the fingers or toes) is important due to its frequency and the few effective treatment options available. The identification of common patient-reported CIPN characteristics and associated functional limitations may help to facilitate patient-clinician discussions of CIPN in practice. AIMS: To quantify the severity, duration, location, characteristics, and associated functional limitations of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving neurotoxic chemotherapy. DESIGN: Exploratory secondary analysis of a prospective, two-phase study SETTING: Breast, gastrointestinal, and multiple myeloma clinics at Dana-Farber Cancer Institute. PARTICIPANTS: 142 individuals who planned to receive at least three more cycles of neurotoxic chemotherapy after consent. METHODS: Participants self-reported CIPN using standardized measures (i.e., PRO-CTCAE™ Numbness and Tingling Items or 0-10 numerical rating scale of worst CIPN pain intensity) and/or study team generated follow up questions about CIPN location, duration, characteristics, and functional limitations prior to three consecutive clinic visits (T1, T2, T3). Participants' responses to the CIPN self-report questionnaires were described by chemotherapy type and age. RESULTS: Over approximately 36.5 days (T1-T3), the percentage of participants reporting at least mild CIPN increased from 59.3% to 71%. At T3, patients with non-painful (n = 98) or painful neuropathy (n = 34) frequently reported symptoms in the fingers (non-painful = 83.5%, painful = 76.5%) or toes (non-painful = 49.5%, painful = 41.2%) and characterized symptoms as numbness (non-painful = 54.1%, painful = 50%) or tingling (non-painful = 68.4%, painful = 82.4%). Self-reported CIPN functional limitations (n = 55) included difficulties with buttoning a shirt (38.2%) or walking (25.5%). Paclitaxel-related CIPN (n = 33) was frequently characterized as "continuous" (30.3%), whereas oxaliplatin-related CIPN (n = 51) was frequently characterized as "intermittent" (41.2%). Young adults (15-39 years old, n = 15) frequently reported moderate-severe non-painful CIPN (46.7%), painful CIPN (40%), and CIPN interference (33.3%). CONCLUSIONS: Consistent with qualitative research, participants frequently described CIPN as numbness and/or tingling in the fingers and/or toes.
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Antineoplásicos , Enfermedades del Sistema Nervioso Periférico , Adolescente , Adulto , Antineoplásicos/efectos adversos , Humanos , Hipoestesia/inducido químicamente , Hipoestesia/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Estudios Prospectivos , Autoinforme , Adulto JovenRESUMEN
CONTEXT: Clinical guidelines are available to enhance symptom management during cancer treatment but often are not used in the practice setting. Clinical decision support can facilitate the implementation and adherence to clinical guidelines. and improve the quality of cancer care. OBJECTIVES: Clinical decision support offers an innovative approach to integrate guideline-based symptom management into oncology care. This study evaluated the effect of clinical decision support-based recommendations on clinical management of symptoms and health-related quality of life (HR-QOL) among outpatients with lung cancer. METHODS: Twenty providers and 179 patients were allotted in group randomization to attention control (AC) or Symptom Assessment and Management Intervention (SAMI) arms. SAMI entailed patient-report of symptoms and delivery of recommendations to manage pain, fatigue, dyspnea, depression, and anxiety; AC entailed symptom reporting prior to the visit. Outcomes were collected at baseline, two, four and six-months. Adherence to recommendations was assessed through masked chart review. HR-QOL was measured by the Functional Assessment of Cancer Therapy-Lung questionnaire. Descriptive statistics with linear and logistic regression accounting for the clustering structure of the design and a modified chi-square test were used for analyses. RESULTS: Median age of patients was 63 years, 58% female, 88% white, and 32% ≤high school education. Significant differences in clinical management were evident in SAMI vs. AC for all target symptoms that passed threshold. Patients in SAMI were more likely to receive sustained-release opioids for constant pain, adjuvant medications for neuropathic pain, opioids for dyspnea, stimulants for fatigue and mental health referrals for anxiety. However, there were no statistically significant differences in HR-QOL at any time point. CONCLUSION: SAMI improved clinical management for all target symptoms but did not improve patient outcomes. A larger study is warranted to evaluate effectiveness.
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Sistemas de Apoyo a Decisiones Clínicas , Neoplasias Pulmonares , Analgésicos Opioides , Disnea/terapia , Fatiga/terapia , Femenino , Humanos , Neoplasias Pulmonares/psicología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Dolor , Calidad de VidaRESUMEN
MET-targeted therapies are clinically effective in MET-amplified and MET exon 14 deletion mutant (METex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones in vitro The combination of capmatinib/merestinib was evaluated in vivo and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate in vitro and in vivo that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.
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Resistencia a Antineoplásicos/efectos de los fármacos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Simulación del Acoplamiento Molecular/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Femenino , Humanos , Ratones , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
In a sample of individuals with ovarian cancer, we aimed to (a) identify factors associated with the psychosocial impact of genetic counseling and multigene panel testing, (b) identify factors associated with cancer genetics knowledge, and (c) summarize patient-reported recommendations to improve the genetic counseling and multigene panel testing process. Eligible participants in this secondary analysis of quantitative and qualitative survey data were English-speaking adults with ovarian cancer. Psychosocial impact was assessed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire. Knowledge of cancer genetics was assessed using the KnowGene scale. Significant predictors of MICRA and KnowGene scores were identified using multiple regression. Open-ended survey item responses were analyzed using conventional content analysis. Eighty-seven participants met eligibility criteria. A positive genetic test result was associated with greater adverse psychosocial impact (B = 1.13, p = 0.002). Older age (B = - 0.07, p = 0.044) and being a member of a minority racial or ethnic group (B = - 3.075, p = 0.033) were associated with lower knowledge, while a personal history of at least one other type of cancer (B = 1.975, p = 0.015) was associated with higher knowledge. In open-ended item responses, participants wanted clinicians to assist with family communication, improve result disclosure, and enhance patient and family understanding of results. A subset of individuals with ovarian cancer who receive a positive genetic test result may be at risk for adverse psychosocial outcomes. Tailored cancer genetics education is necessary to promote the equitable uptake of targeted ovarian cancer treatment and risk-reducing therapies. Interventions to enhance patient-clinician communication in this setting are a research priority.
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Neoplasias de la Mama , Neoplasias Ováricas , Adulto , Neoplasias de la Mama/genética , Carcinoma Epitelial de Ovario/genética , Femenino , Asesoramiento Genético/psicología , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/psicologíaRESUMEN
In a comparative oncology study with progression-free or overall survival as the endpoint, the primary or key secondary analysis is routinely stratified by patients' baseline characteristics when evaluating the treatment difference. The validity of a conventional strategy such as a stratified HR analysis depends on stringent model assumptions that are unlikely to be met in practice, especially in immunotherapy studies. Thus, the resulting summary is generally neither valid nor interpretable. This article discusses issues with conventional stratified analyses and presents alternatives using data from KEYNOTE-189, a recent immunotherapy trial for treating patients with metastatic, non-squamous, non-small-cell lung cancer.
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Ensayos Clínicos como Asunto/métodos , Inmunoterapia/métodos , Oncología Médica/métodos , HumanosRESUMEN
BACKGROUND: Timely detection of chemotherapy-induced peripheral neuropathy (CIPN) is critical to effectively tailor chemotherapy dose levels and offer supportive care. The purpose of this secondary analysis was to determine the reliability and validity of the two Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) numbness and tingling severity and interference items to screen for CIPN in patients receiving taxanes, platinums, or proteasome inhibitors. METHODS: Participants (N = 142) completed the two PRO-CTCAE items, a 0-10 numerical rating scale of worst CIPN pain intensity, and the Quality of Life Questionnaire-CIPN20 (QLQ-CIPN20) prior to three clinical visits (T1, T2, T3) during neurotoxic chemotherapy. Participants completed the two PRO-CTCAE items again following the T3 clinical visit (T4). In addition, study staff administered the modified Total Neuropathy Score-Clinical Version (TNSc©) at T3. We examined floor (i.e., no CIPN severity or interference) and ceiling effects, test-retest reliability, concurrent validity, longitudinal validity, construct validity of the response categories, and sensitivity and specificity of the two PRO-CTCAE items. RESULTS: At T3, 29% of participants had PRO-CTCAE severity scores at the floor; 60.1% of participants reported interference item scores at the floor. Agreements between scores reported at T3 and T4 for PRO-CTCAE severity (ICC = 0.79) and interference (ICC = 0.73) were moderate to strong. The PRO-CTCAE severity and interference items correlated moderately-strongly with QLQ-CIPN20 sensory (Spearman's ρ-range = 0.53-0.72) and motor (Spearman's ρ-range = 0.50-0.58) subscale scores. The Cohen's d from T1 to T3 for the PRO-CTCAE items were small (severity: d = 0.32, interference: d = 0.40) and comparable to the effect sizes for change observed with the QLQ-CIPN20. The PRO-CTCAE severity (0-3) and interference (0-2) response categories distinguished respondents with significantly different levels of QLQ-CIPN20 sensory and motor subscale scores (p < 0.001 via Jonckheere-Terpstra tests). The sensitivity and specificity of the PRO-CTCAE severity item (cutoff > 0) to detect probable sensory peripheral neuropathy were 95.83% and 65.22%, while the sensitivity and specificity of the PRO-CTCAE™ interference item (cutoff > 0) were 51.39% and 73.91%. CONCLUSION: Preliminary evidence supports the reliability and validity of the PRO-CTCAE numbness and tingling items for CIPN screening, although there may be floor effects and limitations in the capacity of the PRO-CTCAE items to identify the full range of CIPN sensory and motor features beyond numbness and tingling. Trial Registration ClinicalTrials.Gov, NCT03514680. Registered 21 April 2018. https://clinicaltrials.gov/ct2/show/NCT03514680.
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INTRODUCTION: Remote consent and enrollment offer a unique opportunity to provide rare cancer populations with access to clinical research. The genomic analysis of plasma cell-free DNA (cfDNA) permits remote characterization of the cancer genome. We hypothesized we could leverage these approaches to remotely study drug resistance in patients with metastatic ALK-positive NSCLC. METHODS: The SPACEWALK study (Study of Plasma Next-Generation Sequencing for Remote Assessment, Characterization, Evaluation of Patients With ALK Drug Resistance) enrolled patients with ALK-positive NSCLC and progression on a next-generation ALK inhibitor who could participate remotely. Plasma was collected for next-generation sequencing (NGS) of cfDNA before initiating subsequent therapy, with results returned and subsequent therapy studied. RESULTS: Of the 62 patients enrolled, an ALK fusion was detected in 27 (44%) with a median allelic fraction of 2.6%. Among these 27 patients, a potential resistance mechanism was identified in 17 patients (63%): eight cases (30%) had secondary ALK kinase domain resistance mutations, three cases (11%) had bypass track resistance, and six cases (22%) had both ALK resistance mutations and bypass resistance. The most frequently detected mechanism of bypass resistance was MET amplification. Repeat plasma NGS was performed in 14 patients after subsequent treatment was initiated, with seven (50%) patients exhibiting greater than 50% reductions in ALK fusion allelic fraction. CONCLUSIONS: Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response.
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OBJECTIVE: To describe perceptions of patient-centered communication (PCC); assess whether physician specialty, patient characteristics, or health system characteristics are associated with PCC; and identify associations between PCC, health-related quality of life (HRQoL), and symptom burden among individuals with ovarian cancer. METHODS: Cross-sectional, descriptive survey of English-speaking adults with ovarian cancer. PCC, HRQoL, and ovarian cancer symptom burden were assessed with the PCC-Ca-36, the FACT-G, and the FOSI-18, respectively. PCC-Ca-36 scores were summarized using descriptive statistics. Predictors of PCC-Ca-36, FACT-G, and FOSI-18 scores were identified using multiple linear regression. RESULTS: Participants (n = 176) had a mean age of 59.4 years (SD = 12.1). The majority (65.9%) had advanced-stage disease, while 42.0% were receiving treatment. The mean PCC-Ca-36 total score was 4.09 (SD = 0.78) out of a possible 5, indicating participants often perceived that clinicians engaged in PCC. Among the PCC functions, participants reported that clinicians least often enabled patient self-management (M = 3.65, SD = 0.99), responded to emotions (M = 3.84, SD = 1.04), and managed uncertainty (M = 3.91, SD = 0.93). In multivariable analyses, neither physician specialty nor patient and health system characteristics were significantly associated with overall PCC. Greater overall PCC predicted better overall HRQoL; better social/family, emotional, and functional well-being; and lower overall and physical symptom burden (all p ≤ 0.05). CONCLUSION: Greater PCC is significantly associated with better HRQoL and lower symptom burden among individuals with ovarian cancer. PRACTICE IMPLICATIONS: Promotion of PCC is a promising strategy to improve patient-reported outcomes in the ovarian cancer care setting.
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Costo de Enfermedad , Neoplasias Ováricas/psicología , Medición de Resultados Informados por el Paciente , Relaciones Médico-Paciente , Calidad de Vida , Anciano , Comunicación , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Atención Dirigida al Paciente , Investigación Cualitativa , Autoinforme , IncertidumbreRESUMEN
The objectives of the study were to characterize the tumor burden dynamics on serial computed tomography scans in patients with advanced non-small-cell lung cancer treated with first-line pembrolizumab and to identify imaging markers for prolonged overall survival (OS). MATERIALS AND METHODS: Eighty-eight patients treated with first-line pembrolizumab monotherapy were evaluated on serial computed tomography scans to characterize their quantitative tumor burden during therapy. Tumor burden dynamics were studied for the association with OS. RESULTS: The overall response rate was 42% (37/88), with the median tumor burden changes at the best overall response of -18.3% (range, -100.0% to +103.6%). Response rates were higher in men than in women (P = .05) and in patients with higher programmed cell death ligand-1 expression levels (P = .02). Tumor burden stayed below the baseline burden throughout therapy in 55 patients (63%). In an 8-week landmark analysis, patients with tumor burden below the baseline burden during the first 8 weeks of therapy had longer OS compared with patients who had ≥ 0% increase (median OS, 30.7 v 16.2 months; hazard ratio [HR] = 0.44; P = .01). In the extended Cox models, patients whose tumor burden stayed below the baseline burden throughout therapy had significantly reduced hazards of death (HR = 0.41, P = .003, univariate; HR = 0.35, P = .02, multivariate). Only one patient (1.1%) experienced pseudoprogression with initial tumor increase and subsequent tumor regression. CONCLUSION: In patients with advanced non-small-cell lung cancer treated with first-line single-agent pembrolizumab, tumor burden reduction below the baseline burden during therapy was an independent marker for prolonged OS, which may serve as a practical guide for treatment decisions.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de Supervivencia , Carga TumoralRESUMEN
Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.This article is highlighted in the In This Issue feature, p. 1861.