Showing papers by "Aminah Jatoi published in 2017"

Accrual of Older Patients With Breast Cancer to Alliance Systemic Therapy Trials Over Time: Protocol A151527

Abstract: Purpose Despite increasing awareness of accrual challenges, it is unknown if accrual of older patients to breast cancer treatment trials is improving. Methods We examined accrual of older patients to Alliance for Clinical Trials in Oncology systemic therapy breast cancer trials during 1985-2012 and compared disease characteristics and reasons for therapy cessation for older (age ≥ 65 years and ≥ 70 years) versus younger (age < 65 years and < 70 years) participants. To examine accrual trends, we modeled age as a function of time, using logistic regression. Results Overall, 17% of study participants were ≥ 65 years of age. Approximately 15%, 24%, and 24% of participants in adjuvant, neoadjuvant, and metastatic trials were age ≥ 65 years, and 7%, 15%, and 13% were age ≥ 70 years, respectively. The odds of a patient age ≥ 65 years enrolling significantly increased over time for adjuvant trials (odds ratio [OR] per year, 1.04; 95% CI, 1.04 to 1.05) but decreased significantly for neoadjuvant and metastatic trials (OR, 0.62; 95% CI, 0.58 to 0.67 and OR, 0.98, 95% CI, 0.97 to 1.00). Similar trends were seen for those age ≥ 70 years but these were statistically significant for adjuvant and neoadjuvant trials only (OR, 1.05, 95% CI, 1.04 to 1.07; and OR, 0.57, 95% CI, 0.52 to 0.62). In general, those age ≥ 65 years ( v those < 65 years) in adjuvant studies had a higher mean number of lymph nodes involved and more hormone receptor-negative tumors, although tumor sizes were similar. Early protocol treatment cessation was also more frequent in those age ≥ 65 years (50%) versus < 65 years (35.9%) across trials. Conclusion Older patients with breast cancer remain largely underrepresented in cooperative group therapeutic trials. We observed some improvement in accrual to adjuvant trials but worsening of accrual for neoadjuvant/metastatic trials. Novel strategies to increase accrual of older patients are critical to meaningfully change the evidence base for this growing patient population.

EGFR as a prognostic biomarker and therapeutic target in ovarian cancer: evaluation of patient cohort and literature review.

Abstract: Background Limited effectiveness of therapeutic agents targeting epidermal growth factor receptor (EGFR) in clinical trials using unselected ovarian cancer patients has prompted efforts to more effectively stratify patients who might best benefit from these therapies. A series of studies that have evaluated immunohistochemical (IHC) staining of EGFR in ovarian cancer biopsies has produced unclear results as to the utility of this measure as a prognostic biomarker. Here, we used one of the largest, single institution cohorts to date to determine possible associations of EGFR expression with patient outcome. Methods We performed IHC staining of EGFR in tissue microarrays including nearly 500 patient tumor samples. Staining was classified by subcellular localization (membranous, cytoplasmic) or by automated image analysis algorithms. We also performed a literature review to place these results in the context of previous studies. Results No significant associations were found between EGFR subcellular localization or expression and histology, stage, grade, or outcome. These results were broadly consistent with the consensus of the reviewed literature. Conclusions These results suggest that IHC staining for EGFR may not be a useful prognostic biomarker for ovarian cancer patients. Future studies should pursue other staining methods or analysis in combination with other pathway mediators.

North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic‐based dosing of irinotecan, oxaliplatin, and capecitabine as first‐line therapy for patients with advanced small bowel adenocarcinoma

Abstract: BACKGROUND Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used as first-line therapy for patients with small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. The authors performed a phase 2 cooperative group study (North Central Cancer Treatment Group N0543, Alliance) using genotype-dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genotype to test: 1) whether the addition of irinotecan would improve outcomes; and 2) whether UGT1A1 genotype-based dosing could optimize tolerability. METHODS Previously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2-15) in a 21-day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7). RESULTS A total of 33 patients (17 with the 6/6 genotype, 10 with the 6/7 genotype, and 6 with the 7/7 genotype) were enrolled from October 2007 to November 2013; 73% were male, with a mean age of 64 years (range, 41-77 years). Location of the primary tumor included the duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% confidence interval, 21%-56%), with a median progression-free survival of 8.9 months and a median overall survival of 13.4 months. Neither hematologic toxicity (grade ≥3 in 52.9%, 30.0%, and 33.3%, respectively, of the 6/6, 6/7, and 7/7 genotype groups) nor tumor response rate (41.2%, 33%, and 33%, respectively) were found to differ significantly by UGT1A1 genotype. CONCLUSIONS UGT1A1 genotype-directed dosing (gCAPIRINOX) appears to be feasible with favorable rates of hematologic toxicity compared with prior 3-drug studies in unselected patients. Larger studies would be needed to determine the regimen's comparability to oxaliplatin and capecitabine (CapeOx) alone or if response/toxicity differs among patients with different UGT1A1 genotypes. Cancer 2017;123:3494-501. © 2017 American Cancer Society.

The impact of a spiritual legacy intervention in patients with brain cancers and other neurologic illnesses and their support persons

Abstract: Objective The objectives were to assess the feasibility of using a novel, comprehensive chaplain-led spiritual life review interview to develop a personal Spiritual Legacy Document (SLD) for persons with brain tumors and other neurodegenerative diseases and to describe spiritual well-being (SWB), spiritual coping, and quality of life (QOL) of patients and their support persons (SP) before and after receipt of the SLD. Methods Patient-SP pairs were enrolled over a 2-year period. Assessments included the Functional Assessment of Chronic Illness Therapy-Spiritual Expanded Version, Brief Religious Coping Scale, Brief COPE Inventory, and QOL Linear Analog Scale. Baseline assessments were completed prior to an audio-recorded spiritual life review interview with a chaplain. Results Thirty-two patient/SP pairs were enrolled; 27 completed baseline assessments and the interview. Twenty-four reviewed their SLD and were eligible for follow-up. A total of 15 patients and 12 SPs completed the 1-month follow-up; 10 patients and seven SPs completed the 3-month follow-up. Patients endorsed high levels of SWB and spiritual coping at baseline. Both patients and SPs evidenced improvement on several aspects of SWB, spiritual coping, and QOL at 1 month, but patients' decreased financial well-being was also observed. Patients and SPs demonstrated favorable changes in peacefulness and positive religious coping at both time points. Conclusions A chaplain-led spiritual life review is a feasible intervention for patients with neurodegenerative disease and results in beneficial effects on patients and SPs. Copyright © 2015 John Wiley & Sons, Ltd.

Overcoming obstacles in the design of cancer anorexia/weight loss trials.

Abstract: Most advanced cancer patients suffer loss of appetite (anorexia) and loss of weight. Despite the fact that cancer anorexia and weight loss are associated with a poor prognosis and detract from quality of life, no interventions have been demonstrated to palliate this syndrome in its entirety, particularly in patients with treatment-refractory malignancies. Recently, two registration trials - one with anamorelin and another with enobosarm - failed to reach their primary endpoints, thus raising questions. Were both these agents ineffective? Alternatively, did study design issues compromise the ability of these trials to identify effective agents? Thus, this review is timely insofar it serves as an introduction to study design, offers guidance on how to test promising agents for cancer anorexia/weight loss, and provides advice for overcoming trial design obstacles.

Risk of acute myeloid leukemia and myelodysplastic syndrome among older women receiving anthracycline-based adjuvant chemotherapy for breast cancer on Modern Cooperative Group Trials (Alliance A151511)

Abstract: We examined acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) events among 9679 women treated for breast cancer on four adjuvant Alliance for Clinical Trials in Oncology trials with >90 months of follow-up in order to better characterize the risk for AML/MDS in older patients receiving anthracyclines. We used multivariable Cox regression to examine factors associated with AML/MDS, adjusting for age (≥65 vs. <65 years; separately for ≥70 vs. <70 years), race/ethnicity, insurance, performance status, and anthracycline receipt. We also examined the effect of cyclophosphamide, the interaction of anthracycline and age, and outcomes for those developing AML/MDS. On Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741, 7290 received anthracyclines; 15% were in the age ≥65 and 7% were ≥70. Overall, 47 patients developed AML/MDS (30 AML [0.3%], 17 MDS [0.2%]); 83% of events occurred within 5 years of study registration. Among those age ≥65 and ≥70, 0.8 and 1.0% developed AML/MDS (vs. 0.4% for age <65), respectively. In adjusted analyses, older age and anthracycline receipt were significantly associated with AML/MDS (adjusted hazard ratio [HR] for age ≥65 [vs. <65] = 3.13, 95% confidence interval [CI] 1.18–8.33; HR for anthracycline receipt [vs. no anthracycline] = 5.16, 95% CI 1.47–18.19). There was no interaction between age and anthracycline use. Deaths occurred in 70% of those developing AML/MDS. We observed an increased risk for AML/MDS for older patients and those receiving anthracyclines, though these events were rare. Our results help inform discussions surrounding anticipated toxicities of adjuvant chemotherapy in older patients.

Epigenetics of cancer-associated muscle catabolism.

Abstract: Cancer patients are commonly affected by cachexia, a wasting process involving muscle and fat. Specifically, loss of the muscle compartment has been associated with poor prognosis and suboptimal response to therapy. Nutritional support has been ineffective in treating this process leading to investigations into the underlying molecular processes governing muscle catabolism. In this commentary, we discuss the molecular mechanisms of cancer-associated muscle metabolism and the epigenetic processes responsible for the muscle wasting phenotype. Ultimately, we highlight how the epigenome may serve as a promising therapeutic target in reversing cancer-associated muscle catabolism.

Using ePrognosis to estimate 2-year all-cause mortality in older women with breast cancer: Cancer and Leukemia Group B (CALGB) 49907 and 369901 (Alliance A151503).

Abstract: Tools to estimate survival, such as ePrognosis ( http://eprognosis.ucsf.edu/carey2.php ), were developed for general, not cancer, populations. In older patients with breast cancer, accurate overall survival estimates would facilitate discussions about adjuvant therapies. Secondary analyses were performed of data from two parallel breast cancer studies (CALGB/Alliance 49907/NCT000224102 and CALGB/Alliance 369901/NCT00068328). We included patients (n = 971) who were age 70 years and older with complete baseline quality of life data (194 from 49907; 777 from 369901). Estimated versus observed all-cause two-year mortality rates were compared. ePrognosis score was calculated based on age, sex, and daily function (derived from EORTC QLQ-C30). ePrognosis scores range from 0 to 10, with higher scores indicating worse prognosis based on mortality of community-dwelling elders and were categorized into three groups (0–2, 3–6, 7–10). Observed mortality rates were estimated using Kaplan–Meier methods. Patient mean age was 75.8 years (range 70–91) and 73% had stage I–IIA disease. Most patients were classified by ePrognosis as good prognosis (n = 562, 58% 0–2) and few (n = 18, 2% 7–10) poor prognosis. Two-year observed mortality rates were significantly lower than ePrognosis estimates for patients scoring 0–2 (2% vs 5%, p = 0.001) and 3–6 (8% vs 12%, p = 0.01). The same trend was seen with scores of 7–10 (23% vs 36%, p = 0.25). ePrognosis tool only modestly overestimates mortality rate in older breast cancer patients enrolled in two cooperative group studies. This tool, which estimates non-cancer mortality risk based on readily available clinical information may inform adjuvant therapy decisions but should be validated in non-clinical trial populations.

Genetically Predicted Telomere Length is not Associated with Pancreatic Cancer Risk.

Abstract: Background: Epidemiologic associations of leukocyte telomere length (LTL) and pancreatic ductal adenocarcinoma (PDAC) have been inconsistent owing, in part, to variation in telomere length (TL) assessment across studies. To overcome this limitation and address concerns of potential reverse causation, we used carriage of telomere-related alleles to genetically predict TL and examined its association with PDAC.Methods: A case-control study of 1,500 PDAC cases and 1,500 controls, frequency-matched on age and sex was performed. Eight of nine polymorphisms previously associated with variation in LTL were analyzed. Genetic risk scores (GRS) consisting of the TL-related polymorphisms were computed as the number of long TL alleles carried by an individual scaled to published kilobase pairs of TL associated with each allele. Participants were further categorized on the basis of the number of short TL alleles they carry across all eight SNPs. Associations were examined in additive and dominant models using logistic regression to calculate ORs and 95% confidence intervals (CI).Results: In age- and sex-adjusted models, one short TL allele (rs10936599, T) was associated with reduced risk, whereas another short TL allele (rs2736100, A) was associated with increased risk, with per-allele ORs of 0.89 (95% CI, 0.79-0.99) and 1.13 (95% CI, 1.01-1.24), respectively. No association was observed with GRS or short TL allele counts, and no associations were observed in the dominant models.Conclusions: Findings suggest that genetically predicted short TL is not associated with PDAC risk.Impact: Common genetic determinants of short TL do not appear to influence PDAC risk. Cancer Epidemiol Biomarkers Prev; 26(6); 971-4. ©2017 AACR.

I'm Still Me: Inspiration and Instruction from Individuals with Brain Cancer.

Abstract: Individuals with brain cancer face many challenges, including threats to cognition, personality, and sensory and motor functioning. These can alter one's sense of identity and result in despair. Chaplain-led spiritual interviews were conducted with 19 patients with brain cancer as part of a larger spiritual legacy intervention called "Hear My Voice." The majority was female (58%), married (68%) and had aggressive/advanced tumors (63%). Participants were 22-68 years of age and expressed the following religious affiliations: Protestant (42%), Catholic (21%), Muslim (5%), and none (32%). Framework analysis was applied to reduce and understand the interview data. Primary codes were relationships with: God or the spiritual, others, and self. Brain cancer was reported to deepen and enrich patients' commitment to these relationships. Struggle and grief were also revealed. Results suggest the continued vitality, growth and generativity of these participants and provide insight for chaplains and others on the medical team.

Incidence, Characteristics, and Implications of Seizures in Patients With Glioblastoma:

Abstract: Background:Seizures in patients with glioblastoma are associated with worse quality of life. However, their incidence, clinical characteristics, and prognostic implications are less well characterized.Objective:This study was undertaken to provide a contemporary experience along with benchmark data relevant to the above in patients with glioblastoma. It also sought to reexplore improved survival with seizures, as observed by others.Methods:In this single-institution study, patients with glioblastoma from 2010 through 2014 had their medical records reviewed in detail.Results:Among 122 patients, 58 (48%) had a seizure history. Of these, 67% had more than 1, 41% had generalized seizures, and most received antiseizure medication (most commonly levetiracetam). The median survival for patients with seizures was 1.66 years and 0.87 years for those without (hazard ratio for risk of death with seizures: 0.72; 95% confidence interval: 0.43, 1.21; P = .22 by the log-rank test).Conclusion:Seizures are common in patie...

A proof-of-concept trial of protein kinase C iota inhibition with auranofin for the paclitaxel-induced acute pain syndrome

Abstract: Paclitaxel causes the paclitaxel-induced acute pain (PIAP) syndrome. Based on preclinical data, we hypothesized that the protein kinase C (PKC) iota inhibitor, auranofin (a gold salt used for other pain conditions), palliates this pain. In a randomized, double-blinded manner, patients who had suffered this syndrome were assigned a one-time dose of auranofin 6 mg orally on day #2 of the chemotherapy cycle (post-paclitaxel) versus placebo. Patients completed the Brief Pain Inventory and a pain diary on days 2 through 8 and at the end of the cycle. The primary endpoint was pain scores, as calculated by area under the curve, in response to “Please rate your pain by circling the one number that best describes your pain at its worse in the last 24 hours.” Thirty patients were enrolled. For the primary endpoint, mean area under the curve of 55 units (standard deviation 19) and 61 units (standard deviation 22) were observed in auranofin-treated and placebo-exposed patients, respectively (p = 0.44). On day 8 and at the end of the cycle, pain scores in auranofin-treated patients were more favorable, although differences were not statistically significant. In the dose schedule studied, auranofin did not palliate the PIAP syndrome, but delayed beneficial trends suggest further study for this indication.

Lymphedema, musculoskeletal events and arm function in older patients receiving adjuvant chemotherapy for breast cancer (Alliance A171302)

Abstract: Musculoskeletal events (MEs) resulting from breast cancer treatment can significantly interfere with the quality of life (QOL) of older adults. We evaluated the incidence of MEs in women 65 years and older who had surgery and adjuvant chemotherapy for breast cancer, and the impact of treatment on MEs and arm function. Patient-reported data in Alliance/CALGB 49907 were collected using the EORTC QLQ-BR23 and physician-reported adverse events to characterize self-reported MEs and incidence of lymphedema. EORTC QLQ-BR23 items related to musculoskeletal events were analyzed in this study and data collected at study entry (post-operative) and 12 and 24 months post-entry. Lymphedema, arm function, and ME data were available for 321 patients. One or more MEs were reported by 87% (median number = 3) and 64% (median number = 1) of patients post-operatively and at 24 months. At 24 months 2% had persistence of six MEs. Seventy-four percent experienced at least ≥3/6 types of MEs over the 24-month period. Detection of lymphedema at any time during the study was noted in 7.5% of the patients and appeared to be associated with the type of chemotherapy given: CMF 16.4%, capecitabine 5.8%, and AC 4%. Mastectomy and axillary node dissection were associated with the most MEs. LROM correlated with poorer arm function at all time periods. Potentially debilitating MEs occur in three-fourths of elderly women undergoing standard therapy for breast cancer. Emphasis should be placed on prevention, identification, and treatment of these MEs to improve QOL.

Comparative “nocebo effects” in older patients enrolled in cancer therapeutic trials: Observations from a 446-patient cohort

Abstract: BACKGROUND A nocebo is an inert substance associated with adverse events. Although previous studies have examined the positive (placebo) effects of such inert substances, few have examined negative (nocebo) adverse event profiles, particularly in older patients who have higher morbidity and can experience frequent and severe adverse events from cancer therapy. METHODS This study focused on placebo/nocebo-exposed patients who participated in 2 double-blind, placebo-controlled, cancer therapeutic studies, namely, North Central Cancer Therapy Group trial NCCTG 97-24-51 and American College of Surgeons Oncology Group trial Z9001, with the goal of reporting the comparative, age-based adverse event rates, as reported during the conduct of these trials. RESULTS Among the 446 patients who received only placebo/nocebo and who were the focus of the current report, 161 were aged ≥65 years at the time of respective trial entry, and 5234 adverse events occurred. Unadjusted adverse event rates did not differ significantly between patients aged ≥65 years and younger patients (rate ratio, 1.01; 99% confidence interval, 0.47-2.02), and the findings were similar findings for grade 2 or worse adverse events and for all symptom-driven adverse events (for example, pain, loss of appetite, anxiety). Adjustment for sex, ethnicity, baseline performance score, and individual trial resulted in no significant age-based differences in adverse event rates. Similar findings were observed with an age threshold of 70 years. CONCLUSIONS Adverse events are equally common in older and younger cancer patients who are exposed to nocebo and thus require the same degree of clinical consideration regardless of age. Cancer 2017;123:4193-4198. © 2017 American Cancer Society.

Molecular Modeling and Functional Analysis of Exome Sequencing-Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma

Abstract: PurposeGenomic testing has increased the quantity of information available to oncologists. Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician’s ability to use these findings to inform treatment. We applied a combination of in silico prediction and molecular modeling tools and laboratory techniques to rapidly define actionable VUSs.Materials and MethodsExome sequencing was conducted on 308 tumors from various origins. Most single nucleotide alterations within gene coding regions were VUSs. These VUSs were filtered to identify a subset of therapeutically targetable genes that were predicted with in silico tools to be altered in function by their variant sequence. A subset of receptor tyrosine kinase VUSs was characterized by laboratory comparison of each VUS versus its wild-type counterpart in terms of expression and signaling activity.ResultsThe study identified 4,327 point mutations of which 3,833 were VUSs. Filtering for mutatio...

Cancer-associated weight loss: releasing its firm grip on negative clinical outcomes.

Abstract: DOI:10.1097/SPC.0000000000000297 What does the future hold for treating weight loss in advanced cancer patients? The past 5 years have yielded immense disappointment in efforts to treat the cancer-associated weight loss syndrome. As reviewed by Garcia (pp. 266–271) in this issue of Current Opinions in Supportive and Palliative Care, two large registration trials, which, in total, included over 1500 patients and cost an estimated $100 million, failed to achieve their primary dual endpoints [1,2]. Neither of these trials – one which tested the selective androgen receptor modulator, enobosarm, and the other which tested the oral ghrelin mimetic, anamorelin – resulted in a prescribable agent, leading to the same stagnant conclusion that modest palliation with older agents, such as progesterones and corticosteroids, remains the only proven therapeutic approach for select weight-losing cancer patients with an incurable malignancy [3,4]. For example, in the anamorelin trials, it was an absence of improvement in hand grip strength that led to disappointment. In essence, over the past 4 decades, the standard of care for treating cancer-associated weight loss in incurable cancer patients remains unchanged. Hence, the question posed above is not only provocative but also relevant and timely. In this issue of the journal, investigators begin to ponder this question further. Summarizing a compendium of previously published data, Lau and Iyengar (pp. 261–265) take the novel approach of focusing on weight loss in cancer patients who are receiving radiation. Only recently, Fakhry et al. [5] added yet another such study that looks at radiation in over 600 patients with oropharyngeal cancer and observed that weight loss is associated with shorter cancer progression-free survival. Such studies join countless others that have reached the exact same conclusion: weight loss in cancer patients is associated with poor clinical outcomes. However, this focus on radiation-treated cancer patients is innovative; it draws attention to cancer patients who often receive aggressive multimodality therapy, suffer high rates of severe weight loss, and yet appear to be a captive audience for a therapeutic intervention to help manage weight loss because of daily travel to the clinic to receive radiation treatments.

Prescriber adherence to antiemetic guidelines with the new agent trifluridine-tipiracil

Abstract: Cancer drugs are becoming available at an unprecedented rate. In 2015 alone, the US Food and Drug Administration (FDA) approved 18 new agents.1 Although many of those agents have adverse event profiles that are more favorable than those seen with conventional chemotherapy, nausea and vomiting still occur. In fact, nausea and vomiting continue to be ranked as among the most common and distressing of cancer symptoms.2,3 In a 2004 study, Grunberg and colleagues reported that as many as 75% of health care providers misjudge the risk for chemotherapy-induced nausea and vomiting (CINV), even when prescribing cancer drugs that have been available for years,4 thus amplifying concerns that such risk assessment might be even worse when new cancer agents are prescribed for the first time. In this study, we hypothesized that patients prescribed a new cancer drug, trifluridine-tipiracil, would be at risk for CINV because of poor guideline adherence on the part of health care providers. The correct matching of antiemetics to chemotherapy is important. Inadequate antiemetic prophylaxis predisposes to nausea and vomiting with dehydration and met-