AbstractBackground.Incorporation of next‐generation sequencing (NGS) technology into clinical utility in targeted and immunotherapies requires stringent validation, including the assessment of tumor mutational burden (TMB) and microsatellite instability (MSI) status by NGS as important biomarkers for response to immune checkpoint inhibitors.Materials and Methods.We designed an NGS assay, Cancer Sequencing YS panel (CSYS), and applied algorithms to detect five classes of genomic alterations and two genomic features of TMB and MSI.Results.By stringent validation, CSYS exhibited high sensitivity and predictive positive value of 99.7% and 99.9%, respectively, for single nucleotide variation; 100% and 99.9%, respectively, for short insertion and deletion (indel); and 95.5% and 100%, respectively, for copy number alteration (CNA). Moreover, CSYS achieved 100% specificity for both long indel (50–3,000 bp insertion and deletion) and gene rearrangement. Overall, we used 33 cell lines and 208 clinical samples to validate CSYS's NGS performance, and genomic alterations in clinical samples were also confirmed by fluorescence in situ hybridization, immunohistochemistry, and polymerase chain reaction (PCR). Importantly, the landscape of TMB across different cancers of Chinese patients (n = 3,309) was studied. TMB by CSYS exhibited a high correlation (Pearson correlation coefficient r = 0.98) with TMB by whole exome sequencing (WES). MSI measurement showed 98% accuracy and was confirmed by PCR. Application of CSYS in a clinical setting showed an unexpectedly high occurrence of long indel (6.3%) in a cohort of tumors from Chinese patients with cancer (n = 3,309), including TP53, RB1, FLT3, BRCA2, and other cancer driver genes with clinical impact.Conclusion.CSYS proves to be clinically applicable and useful in disclosing genomic alterations relevant to cancer target therapies and revealing biomarkers for immune checkpoint inhibitors.Implications for Practice.The study describes a specially designed sequencing panel assay to detect genomic alterations and features of 450 cancer genes, including its overall workflow and rigorous clinical and analytical validations. The distribution of pan‐cancer tumor mutational burden, microsatellite instability, gene rearrangement, and long insertion and deletion mutations was assessed for the first time by this assay in a broad array of Chinese patients with cancer. The Cancer Sequencing YS panel and its validation study could serve as a blueprint for developing next‐generation sequencing‐based assays, particularly for the purpose of clinical application.
A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2‐Positive Metastatic Breast Cancer (CCTG IND.229)
AbstractBackground.Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD‐L1)‐positive, triple‐negative, metastatic breast cancer (MBC). Antibody‐dependent cell‐mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2‐positive MBC previously treated with chemotherapy and anti‐HER2 antibodies to assess safety, efficacy, and correlative endpoints.Patients and Methods.Patients with HER2‐positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D.Results.Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40–86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab‐emtansine (93%) for MBC. No dose‐limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade ≥3 immune‐related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD‐L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on‐treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration.Conclusion.The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2‐positive PD‐L1‐negative MBC.Implications for Practice.This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2‐positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2‐positive programmed death ligand 1 (PD‐L1)‐negative MBC with evidence of cytotoxic T‐cell exhaustion. Furthermore, all patients had no expression of PD‐L1 in the tumor cells. These data support the importance of PD‐L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the “cold” tumors to be able to combine current immune‐oncology agents.
A Randomized, Double‐Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX‐427) in Patients with Previously Untreated Stage IV Non‐Squamous‐Non‐Small‐Cell Lung Cancer: The SPRUCE Trial
AbstractBackground.This randomized, double‐blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non‐small cell lung cancer (NSCLC).Methods.Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21‐day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression‐free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity.Results.The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment‐related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months.Conclusion.The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first‐line setting.Implications for Practice.This randomized, double‐blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non‐small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first‐line setting.
Acceptability of Routine Evaluations Using Patient‐Reported Outcomes of Common Terminology Criteria for Adverse Events and Other Patient‐Reported Symptom Outcome Tools in Cancer Outpatients: Princess Margaret Cancer Centre Experience
AbstractBackground.Recent studies have demonstrated improved outcomes with real‐time patient‐reported outcome questionnaires (PRO questionnaires) using questions adapted for patient use from the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Outside of the clinical trial setting, limited information exists on factors affecting the completion of PRO questionnaires in routine practice. The primary aim of this prospective cross‐sectional study was to evaluate patient willingness to complete PRO questionnaires on a regular basis and to better understand responder biases to improve patient feedback.Materials and Methods.Patients performing PRO‐CTCAE toxicity and symptom PRO questionnaires in oncology clinics at Princess Margaret Cancer Centre from 2013 to 2016 were assessed for their willingness to complete PRO questionnaires using a nine‐item, tablet‐based acceptability survey. Patient‐reported characteristics (i.e., age, sex, language, marital status, education, occupation, etc.), cancer type, treatment modalities, and health metrics (i.e., Eastern Cooperative Oncology Group) were also collected. Characteristics were evaluated by logistic regression (odds ratios [OR]) using the primary outcome with prespecified levels of significance for univariate (p ≤ .10), and additional multivariate (p ≤ .05) testing.Results.A total of 1,792 patients (median age 60 years; range 18–97) with various cancer diagnoses were assessed. A greater proportion of female (56%) and white (74%) respondents with an annual household income of <$100,000 (69%) participated. More than half (58%) of respondents were willing to complete PRO questionnaires at every clinic visit, and a high proportion (77%) found utility in reporting physical and emotional feelings to clinicians using PRO questionnaires. In general, patients did not find that PRO questionnaires made clinic visits more difficult (93%). In uni‐ and multivariable testing, patients were more willing to complete sleep‐ and fatigue‐related PRO questionnaires relative to chemotoxicity‐based PRO questionnaires (OR 1.52; p = .012). Patients aged 40–65 versus 18–40 years were also more likely to report high PRO questionnaire acceptability (OR 1.49; p = .025). Additional patient characteristics such as white ethnicity (OR 1.76), Canada as country of birth (OR 1.66), and English language (OR 2.15) relative to other had higher acceptability on uni‐ (p < .001) and multivariable (p < .001) analyses. Patients reporting treatment intent as palliative (OR 0.69; p = .0013) or hematological (OR 0.73; p = .027) were less likely to report high PRO questionnaire acceptability on univariable analysis; however, only palliative patients (OR 0.72) maintained this effect on multivariable testing (p = .012). Patients reporting higher health utility scores (per change in .05) also had significantly increased PRO questionnaire acceptability in uni‐ (OR 1.06; p < .001) and multivariable (OR 1.05; p = .008) analyses. No significant differences in PRO questionnaire acceptability were seen between cancer types, education level, household income, employment status, or treatment modality.Conclusion.Routine assessment using PRO questionnaires is associated with moderate acceptability by patients with cancer. Specific patient characteristics are associated with higher completion willingness. Additional research is necessary to identify factors associated with low acceptability of PRO questionnaires and to develop site‐, ethnicity‐, and treatment‐specific instruments to assess the value of PRO questionnaires for symptom monitoring in clinical practice.Implications for Practice.This study will help to identify the clinical, demographic, and survey characteristics associated with willingness to complete patient‐reported outcome questionnaires regularly in the cancer outpatient setting.
Cabozantinib Versus Sunitinib for Untreated Patients with Advanced Renal Cell Carcinoma of Intermediate or Poor Risk: Subgroup Analysis of the Alliance A031203 CABOSUN trial
AbstractCabozantinib treatment prolonged progression‐free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number. NCT01835158.
Development and Validation of an Easy‐to‐Implement, Practical Algorithm for the Identification of Molecular Subtypes of Gastric Cancer: Prognostic and Therapeutic Implications
AbstractBackground.Gastric cancer (GC) is a heterogeneous disease, and substantial efforts have been made to develop a molecular biology‐based classification system for GC. Analysis of the genomic signature is not always feasible, and thus, we aimed to (i) develop and validate a practical immunohistochemistry (IHC)‐ and polymerase chain reaction (PCR)‐based molecular classification of GC and (ii) to assess HER2 status according to this classification.Materials and Methods.A total of 894 consecutive patients with GC from two individual cohorts (training, n = 507; validation, n = 387) were classified using Epstein‐Barr virus (EBV) in situ hybridization, microsatellite instability (MSI) testing, and IHC for E‐cadherin and p53.Results.We were able to classify patients into five groups in the training cohort: group 1 (MSI+), group 2 (EBV−, MSI−, non‐epithelial‐mesenchymal transition [non‐EMT]‐like, p53−), group 3 (EBV+), group 4 (EBV−, MSI−, non‐EMT‐like, p53+), and group 5 (EBV−, MSI−, EMT‐like). In the training cohort, each group showed different overall survival (OS) after gastrectomy (p < .001); group 1 had the best prognosis, and group 5 showed the worst survival outcome. The significant impact of the classification system on OS was also verified in the validation cohort (p = .004). HER2 positivity was observed in 6.5% of total population, and most of HER2‐positive cases (93.1%) were included in groups 2 and 4.Conclusion.We developed and validated a modified IHC‐ and PCR‐based molecular classification system in GC, which showed significant impact on survival, irrespective of stage or other clinical variables. We also found close association between HER2 status and non‐EMT phenotype in our classification system.Implications for Practice.Molecular classification of gastric cancer suggested by previous studies mostly relies on extensive genomic data analysis, which is not always available in daily practice. The authors developed a simplified immunohistochemistry‐ and polymerase chain reaction‐based molecular classification of gastric cancer and proved the prognostic significance of this classification, as well as the close association between HER2 status and certain groups of the classification, in the largest consecutive cohort of gastric cancer. Results of this study suggest that this scheme is a cost‐effective, easy‐to‐implement, and feasible way of classifying gastric cancer in daily clinical practice, also serving as a practical tool for aiding therapeutic decisions and predicting prognosis.
Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3‐Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations
AbstractBackground.This multicenter, open‐label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3‐kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations.Materials and Methods.Eighty‐nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0‐2. Binimetinib and buparlisib combinations were explored in patients with KRAS‐, NRAS‐, or BRAF‐mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)‐mutant, advanced non‐small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS‐ or BRAF‐mutant ovarian cancer; or advanced non‐small cell lung cancer with KRAS mutation.Results.At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF‐mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies.Conclusion.Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose‐limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies.Implications for Practice.Because dysregulation of the mitogen‐activated protein kinase (MAPK) and the phosphatidylinositol 3‐kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single‐agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.
Effects of Exercise on Chemotherapy Completion and Hospitalization Rates: The OptiTrain Breast Cancer Trial
AbstractBackground.Exercise during chemotherapy is suggested to provide clinical benefits, including improved chemotherapy completion. Despite this, few randomized controlled exercise trials have reported on such clinical endpoints. From the OptiTrain trial we previously showed positive effects on physiological and health‐related outcomes after 16 weeks of supervised exercise in patients with breast cancer undergoing chemotherapy. Here, we examined the effects of exercise on rates of chemotherapy completion and hospitalization, as well as on blood cell concentrations during chemotherapy.Patients and Methods.Two hundred forty women scheduled for chemotherapy were randomized to 16 weeks of resistance and high‐intensity interval training (RT‐HIIT), moderate‐intensity aerobic and high‐intensity interval training (AT‐HIIT), or usual care (UC). Outcomes included chemotherapy completion, hospitalization, hemoglobin, lymphocyte, thrombocyte, and neutrophil concentrations during chemotherapy.Results.No significant between‐groups differences were found in the proportion of participants who required dose reductions (RT‐HIIT vs. UC: odds ratio [OR], 1.08; AT‐HIIT vs. UC: OR, 1.39), or average relative dose intensity of chemotherapy between groups (RT‐HIIT vs. UC: effect size [ES], 0.08; AT‐HIIT vs. UC: ES, −0.07). A significantly lower proportion of participants in the RT‐HIIT group (3%) were hospitalized during chemotherapy compared with UC (15%; OR, 0.20). A significantly lower incidence of thrombocytopenia was found for both RT‐HIIT (11%) and AT‐HIIT (10%) versus UC (30%; OR, 0.27; OR, 0.27).Conclusion.No beneficial effects of either RT‐HIIT or AT‐HIIT on chemotherapy completion rates were found. However, combined resistance training and high‐intensity interval training were effective to reduce hospitalization rates, and both exercise groups had a positive effect on thrombocytopenia. These are important findings with potential positive implications for the health of women with breast cancer and costs associated with treatment‐related complications.Implications for Practice.Completing the prescribed chemotherapy regimen is strongly associated with a good prognosis for patients with primary breast cancer. Despite this, treatment‐induced side effects make it necessary to reduce or alter the treatment regimen and can also lead to hospitalization. Exercise during chemotherapy is suggested to provide clinical benefits, including improved chemotherapy completion. This study showed that combined resistance and high‐intensity interval training during chemotherapy resulted in lower hospitalization rates and a lower incidence of thrombocytopenia in women with breast cancer undergoing chemotherapy. However, no beneficial effects of either exercise program on chemotherapy completion rates were found, which is in contrast to previous findings in this population. The findings reported in the current article have positive implications for the health of women with breast cancer and costs associated with treatment‐related complications.
AbstractBackground.Molecular analysis has revealed four subtypes of pancreatic ductal adenocarcinoma (PDAC). One subtype identified for the presence of DNA damage repair deficiency can be targeted therapeutically with the poly (ADP‐ribose) polymerase (PARP) inhibitor olaparib. We performed a single institution retrospective analysis of treatment response in patients with PDAC treated with olaparib who have DNA damage repair deficiency mutations.Subjects, Materials, and Methods.Patients with germline or somatic mutations involving the DNA repair pathway were identified and treated with olaparib. The primary objective was to examine the objective response rate (ORR). The secondary objectives were assessing tolerability, overall survival, and change in cancer antigen 19‐9. Quantitative texture analysis (QTA) was evaluated from CT scans to explore imaging biomarkers.Results.Thirteen individuals with metastatic PDAC were treated with Olaparib. The ORR to Olaparib was 23%. Median overall survival (OS) was 16.47 months. Four of seven patients with BRCA mutations had an effect on RAD51 binding, with a median OS of 24.60 months. Exploratory analysis of index lesions using QTA revealed correlations between lesion texture and OS (hepatic lesion tumor texture correlation coefficient [CC], 0.683, p = .042) and time on olaparib (primary pancreatic lesion tumor texture CC, 0.778, p = .023).Conclusion.In individuals with metastatic PDAC who have mutations involved in DNA repair, Olaparib may provide clinical benefit. BRCA mutations affecting RAD51 binding domains translated to improved median OS. QTA of individual tumors may allow for additional information that predicts outcomes to treatment with PARP inhibitors.Implications for Practice.Pursuing germline and somatic DNA sequencing in individuals with pancreatic ductal adenocarcinoma may yield abnormalities in DNA repair pathways. These individuals may receive benefit with poly (ADP‐ribose) polymerase (PARP) inhibition. Radiomics and deep sequencing analysis may yet uncover additional information that may predict outcome to treatment with PARP inhibitors.
Small Cell and Squamous Cell Carcinomas of the Head and Neck: Comparing Incidence and Survival Trends Based on Surveillance, Epidemiology, and End Results (SEER) Data
AbstractBackground.Small cell carcinomas of the head and neck (SmCCHNs) are rare neoplasms with an unfavorable prognosis. Population‐based data describing survival and prognostic factors for SmCCHN are limited.Methods.Data were obtained from the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database for 1973–2013. Patient and tumor‐related characteristics for SmCCHN were compared with those for squamous cell carcinoma of the head and neck (SCCHN). Survival was compared by constructing Kaplan‐Meier curves and Cox proportional hazard models with and without propensity score matching.Results.The data set included 609 SmCCHN and 227,943 SCCHN cases. Both histological subtypes were more common in men than women and more common in white patients. SmCCHN was most likely to originate in the larynx, glottis and hypopharynx, or salivary glands and to present with more advanced stage and grade. SCCHN was most likely to originate in the oral cavity and was found infrequently in the salivary glands. Overall 5‐ and 10‐year survival estimates were 27% and 18% for SmCCHN and 46% and 31% for SCCHN, respectively. In multivariable survival analyses adjusting for age, sex, race, marital status, year of diagnosis, stage, grade, and receipt of radiation, the hazard ratio (HR) comparing SmCCHN with SCCHN was 1.53 with a 95% confidence interval (CI) from 1.39 to 1.68. Average 5‐year survival varied widely between the histologic types when comparing tumor sites: 14.5% for SmCCHN versus 48.9% for SCCHN in the oropharynx. In propensity score matched analyses, the corresponding HR was 1.27 (95% CI, 1.15–1.40).Conclusion.Compared with SCCHN, SmCCHN carries a worse survival and is more likely to present with more advanced stage.Implications for Practice.Small cell carcinoma of the head and neck (SmCCHN) is a rare subtype of head and neck cancer. In this Surveillance, Epidemiology, and End Results (SEER) data analysis, the characteristics and survival of SmCCHN are compared with those of the common squamous cell carcinoma of the head and neck. Results show that SmCCHN carries a worse prognosis and tends to present at a more advanced stage; SmCCHN also is ten times more likely to originate from the salivary glands. These findings may have implications for clinical practice, as location of the tumor may strongly associate with the pathologic diagnosis. If a SmCCHN is diagnosed, a disseminated disease is likely; hence vigilance in staging procedures is indicated.
MET Genomic Alterations in Head and Neck Squamous Cell Carcinoma (HNSCC): Rapid Response to Crizotinib in a Patient with HNSCC with a Novel MET R1004G Mutation
AbstractIdentification of effective targeted therapies for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains an unmet medical need. A patient with platinum‐refractory recurrent oral cavity HNSCC underwent comprehensive genomic profiling (CGP) that identified an activating MET mutation (R1004). The patient was treated with the oral MET tyrosine kinase inhibitor crizotinib with rapid response to treatment.Based on this index case, we determined the frequency of MET alterations in 1,637 HNSCC samples, which had been analyzed with hybrid capture‐based CGP performed in the routine course of clinical care. The specimens were sequenced to a median depth of >500× for all coding exons from 182 (version 1, n = 24), 236 (version 2, n = 326), or 315 (version 3, n = 1,287) cancer‐related genes, plus select introns from 14 (version 1), 19 (version 2), or 28 (version 3) genes frequently rearranged in cancer. We identified 13 HNSCC cases (0.79%) with MET alterations (4 point mutation events and 9 focal amplification events). MET‐mutant or amplified tumors represent a small but potentially actionable molecular subset of HNSCC.Key Points. This case report is believed to be the first reported pan‐cancer case of a patient harboring a MET mutation at R1004 demonstrating a clinical response to crizotinib, in addition to the first documented case of head and neck squamous cell carcinoma (HNSCC) with any MET alteration responding to crizotinib.The positive response to MET inhibition in this patient highlights the significance of comprehensive genomic profiling in advanced metastatic HNSCC to identify actionable targetable molecular alterations as current treatment options are limited.
AbstractPurpose.Older patients with colon cancer (CC) are vulnerable to chemotherapy toxicity and death. Establishing simple scores specific for patients with CC to predict severe chemotoxicity or early death is needed to select the best treatment strategy.Subjects, Materials, and Methods.This prospective multicenter study included patients aged ≥70 years with CC receiving adjuvant or first‐line metastatic chemotherapy. Frailty markers (nutrition, physical activity, energy, mobility, strength), comprehensive geriatric assessment (functional status, comorbidities, falls, nutrition, cognition, and depression), and usual laboratory parameters were collected. Logistic or Cox regression was used to examine at 500 days the association between frailty markers, comprehensive geriatric assessment, laboratory parameters, and grade 3–4 toxicity or death.Results.A total of 97 patients (median age, 79.0 years) received adjuvant (37.1%) or metastatic (62.9%) chemotherapy. During the first 500 days, grade 3–4 toxicity occurred in 49.5%, and 30% died. The predictive model for grade 3–4 toxicity combined (polychemotherapy × 3) + (hypoalbuminemia <32 g/L × 2) + (abnormal grip strength × 1.5) + C‐reactive protein >11 mg/L + Eastern Cooperative Oncology Group performance status (ECOG‐PS), cutoff score >3. The predictive model for death combined (metastasis × 5) + (age × 2) + alkaline phosphatase >100 IU/mL + sex (female) + abnormal grip strength + ECOG‐PS, cutoff score >6. For chemotoxicity prediction, sensitivity was 81.6% and specificity 71.4%. For death prediction, sensitivity was 89.7% and specificity was 83.6%.Conclusion.These simple and efficient “ColonPrediscores” will help to better identify older patients with CC with increased risk of chemotherapy‐related toxicity and/or death.Implications for Practice.The two scores assessed in this study, called “ColonPrediscores”, offer a major advantage in that they do not need a previous complete geriatric assessment, which makes them an easy‐to‐use tool in oncologic settings.
AbstractBackground.Postoperative ambulation recovery after surgery for femur metastases has significant implications for not only the patient's quality of life but also administration of further cancer treatment. Thus, identification of preoperative predictors of ambulation recovery is necessary to set appropriate expectations and guide treatment. This study aimed to assess ambulation recovery rate and identify predictors of ambulation recovery in patients undergoing surgery for femur metastases.Materials and Methods.A total of 244 patients who underwent surgery for femur metastases at our institution were reviewed. Patients were considered ambulatory if they were able to walk independently or walk with aids and nonambulatory if they were wheelchair bound or bedridden. The following potential clinicopathologic factors that might predict postoperative ambulation recovery were evaluated: premorbid general status, cancer burden, and local factors.Results.A total of 165 patients (68%) regained ambulatory status postoperatively. A multivariate analysis revealed poor Eastern Cooperative Oncology Group (ECOG) performance status (odds ratio [OR], 5.327; p < .001) and nonambulatory premorbid ambulatory status (OR, 7.459; p < .001) as independent predictors of poor ambulation recovery after surgery for femur metastases. Postoperative ambulatory status was significantly associated with postoperative survival time (p < .001)Conclusion.Postoperative ambulation recovery rate in our cohort was 68%. Premorbid ambulatory status and ECOG performance status are predictors of ambulation recovery in patients undergoing surgery for femur metastases.Implications for Practice.Postoperative ambulation recovery rate in this cohort was 68%. Premorbid ambulatory status and Eastern Cooperative Oncology Group performance status are predictors of ambulation recovery in patients undergoing surgery for femur metastases.
Serious Cutaneous Toxicities with Immune Checkpoint Inhibitors in the U.S. Food and Drug Administration Adverse Event Reporting System
AbstractCutaneous toxicities frequently occurred with immune checkpoint inhibitors (ICIs), although clinical and pharmacological features are incompletely characterized. The U.S. Food and Drug Administration Adverse Event Reporting System was queried to describe ICI‐related cutaneous toxicities, focusing on severe cutaneous adverse reactions (SCARs): Stevens‐Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. As compared with other anticancer drugs, a higher proportion of death (11.3% vs. 8.7%) and serious reports (42.7% vs. 34.6%) emerged for ICIs (p < .05). A higher frequency of coreported allopurinol and antiepileptics was recorded among 2,525 total SCARs (17% vs. 10%, ICIs and anticancer agents, respectively; p < .05). Mean times to onset were 47, 48, and 40 days (SJS, TEN, and DRESS, respectively), with comparable mean latency between monotherapy and combination regimens (41 days). This immune‐related pattern advocates for long‐lasting monitoring by oncologists and dermatologists.
AbstractBackground.Advanced stage presentation of patients with is common in low‐ and middle‐income countries (LMICs). A comprehensive analysis of existing delays and barriers in LMICs has not been previously reported. We conducted a systematic literature review to comprehensively outline delays and barriers to identify targets for future interventions and provide recommendations for future research in this field.Materials and Methods.Multiple electronic databases were searched using a standardized search strategy. Eligible articles were of any language, from LMICs, and published between January 1, 2002, and November 27, 2017. Included studies reported cancer care intervals or barriers encountered. Intervals and associated barriers were summarized by cancer type and geographical region.Results.This review included 316 study populations from 57 LMICs: 142 (44.9%) studies addressed time intervals, whereas 214 (67.7%) studies described barriers to cancer diagnosis. The median intervals were similar in the following three stages of early diagnosis: (a) access (1.2 months), (b) diagnostic (0.9 months), and (c) treatment (0.8 months). Studies from low‐income countries had significantly longer access intervals (median, 6.5 months) compared with other country income groups. Patients with breast cancer had longer delay intervals than patients with childhood cancer. No significant variation existed between geographic regions. Low health literacy was reported most frequently in studies describing barriers to cancer diagnosis and was associated with lower education level, no formal employment, lower income, and rural residence.Conclusion.Early diagnosis strategies should address barriers during all three intervals contributing to late presentation in LMICs. Standardization in studying and reporting delay intervals in LMICs is needed to monitor progress and facilitate comparisons across settings.Implications for Practice.This review draws the attention of cancer implementation scientists globally. The findings highlight the significant delays that occur throughout the cancer care continuum in low‐ and middle‐income countries and describe common barriers that cause them. This review will help shape the global research agenda by proposing metrics and implementation studies. By demonstrating the importance of standardized reporting metrics, this report sets forth additional research and evidence needed to inform cancer control policies.
AbstractDespite lengthening survival, death rates from metastatic colorectal cancer (CRC) remain unacceptably high, with a bright spot being the demonstration of durable responses in patients with CRC who have mismatch repair‐deficient (dMMR) and/or microsatellite instability‐high (MSI‐H) tumors and are treated with immune checkpoint inhibitor therapy. Nivolumab and pembrolizumab, as well as nivolumab in combination with low‐dose ipilimumab—all checkpoint inhibitors—are currently approved by the U.S. Food and Drug Administration (FDA) for patients with MSI‐H/dMMR metastatic CRC that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Nonetheless, there are a number of questions and considerations in the use of these checkpoint inhibitor therapies. Using a question‐and‐answer format, this review summarizes the scientific rationale for immune checkpoint inhibitor therapy in CRC, including the effects of tumor factors such as genetic aberrations and mutational load on the immune response, particularly in patients with MSI‐H/dMMR disease. We discuss response patterns, response criteria, and immune‐related adverse events using findings from published efficacy and safety data of immune checkpoint inhibitor therapy in metastatic CRC. We also discuss issues surrounding treatment sequencing, incorporating approved checkpoint inhibitors into the current treatment paradigm, and the multiple investigational strategies that may optimize immunotherapy for advanced CRC in the future, including novel combination therapies.Implications for Practice.Colorectal cancer (CRC) is the third most common cancer in the U.S. Despite advances in chemotherapy, survival remains poor for patients with metastatic CRC. Certain immunotherapy agents have demonstrated long‐lasting responses in previously treated patients with immune‐responsive microsatellite instability‐high/mismatch repair‐deficient metastatic CRC, leading to U.S. Food and Drug Administration approval of the immune checkpoint inhibitors nivolumab (with or without low‐dose ipilimumab) and pembrolizumab in this population. Combination therapy (e.g., nivolumab with low‐dose ipilimumab) has demonstrated numerically higher response rates and improved long‐term clinical benefit relative to anti‐programmed death‐1 monotherapy. Ongoing trials are evaluating immunotherapy in the broader CRC population and novel combinations to optimize immunotherapy for advanced CRC.
AbstractLessons Learned. The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment‐related adverse events.Background.As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC).Methods.This was a single‐arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1–14 and intravenous irinotecan at 100mg/m2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen.Results.We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36‐84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3–14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression‐free survival was 9 weeks (range, 3–59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment‐related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3–4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy.Conclusion.Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.
Disparity in Tumor Immune Microenvironment of Breast Cancer and Prognostic Impact: Asian versus Western Populations
AbstractBackground.The clinicopathological features and prognosis of breast cancer in Asia are different from those in the Western countries. Tumor‐infiltrating immune cells can influence the outcome of patients with breast cancer, but they have not been systemically evaluated in Asian patients with breast cancer.Methods.We compared the immune score, composition, and prognostic impact of infiltrating immune cells between Asian and Western patients with breast cancer by analyzing gene expression profiles from eight Gene Expression Omnibus data sets and The Cancer Genome Atlas data set. The Estimation of Stromal and Immune Cells in Malignant Tumours Using Expression Data (ESTIMATE) and Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT) algorithms were used to determine the immune score and composition of tumor‐infiltrating immune cells, respectively.Findings.This study included 462 Asian patients and 2,186 Western patients. Tumors of Asian patients had significantly higher immune score, particularly in the luminal B and HER2‐enriched subtypes. High immune score was associated with favorable prognosis in both Asian and Western patients, and Asian race with a high ESTIMATE immune score provided additional power to predict longer disease‐free survival. Activated CD4 T cells and M2 macrophages were the most strongly associated with survival in both Asian and Western patients.Interpretation.Our study highlights the difference in tumor immune microenvironments between Asian and Western patients. The higher ESTIMATE immune score, which represents more abundant tumor‐infiltrating immune cells, in tumors of Asian patients partly explains their favorable prognosis.Implications for Practice.The tumor microenvironment serves as an interface that affects the human body's reaction to cancer cells. Evidence has revealed that tumor‐infiltrating immune cells were associated with patient prognosis. This study demonstrated the disparity of tumor microenvironments and their prognostic impact between Asian and Western patients with breast cancer. The differences in immune score partially explained the racial survival differences noted in recent studies. Integrated analysis of tumor cells, tumor microenvironment, and racial effect may significantly improve recurrence risk prediction for patients with stage I–III breast cancer. Because the effect of tumor microenvironment varies across different populations, a model of interaction between immune score and race/ethnicity is recommended in accessing the risk of patients with cancer.
Patient‐Reported Factors in Treatment Satisfaction in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
AbstractBackground.Therapy choices in relapsed/refractory multiple myeloma (RRMM) should consider patient satisfaction with treatment, because it is associated with adherence to therapy, health outcomes, and medical safety. The primary objective of this pilot cross‐sectional observational study was to ascertain factors associated with patient‐reported treatment satisfaction in RRMM.Patients and Methods.Patients with a self‐reported diagnosis of RRMM recruited from PatientsLikeMe, MyelomaCrowd, and Facebook were administered an electronic survey that included questions on demographics and clinical history, treatment experience, economic burden, and standardized patient‐reported outcome measures, including the Treatment Satisfaction Questionnaire for Medication, Eastern Cooperative Oncology Group performance status (ECOG PS) measure, and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem V2.0. Univariable and multivariable analyses were used to identify predictors of patient‐perceived treatment satisfaction.Results.One hundred sixty patients with RRMM participated in the study, with a median of two prior relapses and 66.3% reporting the most recent relapse within the last 12 months. ECOG PS ≥2 was associated with lower patient‐reported global satisfaction and perceived effectiveness of current treatment. In addition to shorter time spent receiving therapy, orally administered treatment was the strongest predictor of higher satisfaction with treatment convenience. For patients receiving an injectable drug‐containing regimen versus an all‐oral regimen, respectively, time spent receiving multiple myeloma‐directed therapy was higher (12.6 vs. 4.0 hours per month), and total monthly indirect costs were $1,033 and $241.Conclusion.Poor ECOG PS was linked to reduced treatment satisfaction and perceived effectiveness of current therapy, whereas an all‐oral regimen was associated with increased treatment convenience satisfaction.Implications for Practice.This study suggests that attributes including better Eastern Cooperative Oncology Group performance status, less time spent receiving treatment, and oral route of treatment administration lead to higher patient‐perceived satisfaction with relapsed/refractory multiple myeloma (RRMM) treatment. Oral route of administration was also associated with less time spent receiving treatment and reduced economic burden for patients. Increased attention to these factors in shared treatment decision making is warranted to help identify individual patient needs, preferences, and expectations for RRMM treatments, to resolve dissatisfaction issues, and to improve the experience of patients with RRMM.
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