Short-Term Biomarker Modulation Study of Dasatinib for Estrogen Receptor-Negative Breast Cancer Chemoprevention.

Objective: Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer. Materials and Methods: Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated. Results: Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups. Conclusion: Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention.

Maternal Embryonic Leucine Zipper Kinase is Associated with Metastasis in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSC), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that MELK mRNA levels were higher in TNBC tumors [8.11 (3.79-10.95)] than in HR+HER2- tumors [6.54 (2.90-9.26)]; P < 0.001]. In univariate analysis, patients with breast cancer with high-MELK-expressing tumors had worse overall survival (P < 0.001) and distant metastasis-free survival (P < 0.01) than patients with low-MELK-expressing tumors. In a multicovariate Cox regression model, high MELK expression was associated with shorter overall survival after adjusting for other baseline risk factors. MELK knockdown using siRNA or MELK inhibition using the MELK inhibitor MELK-In-17 significantly reduced invasiveness, reversed epithelial-to-mesenchymal transition, and reduced CSC self-renewal and maintenance in TNBC cells. Nude mice injected with CRISPR MELK-knockout MDA-MB-231 cells exhibited suppression of lung metastasis and improved overall survival compared with mice injected with control cells (P < 0.05). Furthermore, MELK-In-17 suppressed 4T1 tumor growth in syngeneic BALB/c mice (P < 0.001). Our findings indicate that MELK supports metastasis by promoting epithelial-to-mesenchymal transition and the CSC phenotype in TNBC. Significance: These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.

Phase II Trial of Nelipepimut-S Peptide Vaccine in Women with Ductal Carcinoma In Situ.

NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in CTL responses between groups and between pre-vaccination and 1-month post-operation were analyzed using a two-sample t test or Wilcoxon rank sum test. The incidence and severity of adverse events were compared between groups. Overall, 45 patients were registered; 20 patients were HLA-A2 negative, 7 declined participation, 1 withdrew, and 4 failed screening for other reasons. The remaining 13 were randomized to NeuVax (n = 9) or GM-CSF alone (n = 4). Vaccination was well-tolerated with similar treatment-related toxicity between groups with the majority (>89%) of adverse events being grade 1. The percentage of NPS-specific CTLs increased in both arms between baseline (pre-vaccination) and 1-month post-operation. The increase was numerically greater in the NPS+GM-CSF arm, but the difference was not statistically significant. NPS+GM-CSF is safe and well-tolerated when given preoperatively to patients with DCIS. In patients with HLA-A2-positive DCIS, two inoculations with NPS+GM-CSF can induce in vivo immunity and a continued antigen-specific T-cell response 1-month postsurgery. PREVENTION RELEVANCE: This trial showed that vaccination of patients with HLA-A2-positive DCIS with NeuVax in the preoperative setting can induce a sustained antigen-specific T-cell response. This provides proof of principle that vaccination in the preoperative or adjuvant setting may stimulate an adaptive immune response that could potentially prevent disease recurrence.

Phase I Dose Escalation Study of Topical Bexarotene in Women at High Risk for Breast Cancer.

PREVENTION RELEVANCE: Bexarotene is a rexinoid that has been shown to prevent mammary tumors in mouse models but oral dosing has toxicities. This phase I study evaluates topical bexarotene, as a potential chemoprevention agent, for safety and toxicity in high-risk women for breast cancer.

Combination Therapy of Physical Activity and Dexamethasone for Cancer-Related Fatigue: A Phase II Randomized Double-Blind Controlled Trial.

BACKGROUND: Despite the high frequency of cancer-related fatigue (CRF) and its debilitating effects on the quality of life of patients with advanced cancer, there are limited treatment options available. Treatments including physical activity (PA) or dexamethasone (Dex) improve CRF; however, they have lower adherence rates (PA) or long-term adverse effects (Dex). The aim of this study was to determine the feasibility of and preliminary results for the combination of PA and Dex in improving CRF. METHODS: In this phase II randomized controlled trial, patients with advanced cancer and CRF scores of ≥4/10 on the Edmonton Symptom Assessment Scale were eligible. Patients were randomized to standardized PA for 4 weeks with either 4 mg of Dex (LoDex arm) or 8 mg of Dex (HiDex arm) twice a day for 7 days. Feasibility and change in the Functional Assessment of Cancer Illness Therapy-Fatigue subscale (FACIT-F) from baseline to day 8 and day 29 (primary outcome) were assessed. Secondary outcomes included changes in fatigue dimensions (FACIT-General, Patient-Reported Outcomes Measurement Information System [PROMIS]-Fatigue). RESULTS: A total of 60 of 67 (90%) patients were evaluable. All patients were adherent to study medication. We found that 84% and 65% of patients in the LoDex arm and 96% and 68% of patients in the HiDex arm were adherent to aerobic and resistance exercise, respectively. The FACIT-F effect size in the LoDex arm was 0.90 (P<.001) and 0.92 (P<.001) and the effect size in the HiDex arm was 0.86 and 1.03 (P<.001 for both) at days 8 and 29, respectively. We found significant improvements in the Functional Assessment of Cancer Therapy-Physical (P≤.013) and the PROMIS-Fatigue (P≤.003) at days 8 and 29 in both arms. Mixed-model analysis showed a significant improvement in the FACIT-F scores at day 8 (P<.001), day 15 (P<.001), and day 29 (P=.002). Changes in the FACIT-F scores were not significantly different between patients in the 2 arms (P=.86). CONCLUSIONS: Our study found that the combination therapy of PA with Dex was feasible and resulted in the improvement of CRF. The improvement was seen for up to 3 weeks after the discontinuation of Dex. Further larger studies are justified. CLINICALTRIALS: gov identifier: NCT02491632.

A phase II study of talimogene laherparepvec for patients with inoperable locoregional recurrence of breast cancer.

Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3-8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63-NA) and 361 days (95% CI, 240-NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.

Phase II trial of proton therapy versus photon IMRT for GBM: secondary analysis comparison of progression-free survival between RANO versus clinical assessment.

BACKGROUND: This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO). METHODS: Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. "Clinical progression" was based on a clinical radiology report of progression and/or change in treatment for progression. RESULTS: Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4-14.7) months; 10.8 months IMRT versus 11.2 months PT (P = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT (P = .24). RANO-PFS was significantly shorter than clinical PFS overall (P = .001) and for both the IMRT (P = .01) and PT (P = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria. CONCLUSIONS: Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.

Patient-Reported Continuity of Care and Functional Safety Concerns After Inpatient Cancer Rehabilitation.

BACKGROUND: Patients with cancer have been noted to have inadequate continuity of care after discharge from hospital. We sought to assess patient-reported continuity of care and functional safety concerns after acute inpatient rehabilitation. METHODS: This was a prospective study that used cross-sectional surveys at a National Cancer Institute Comprehensive Cancer Center. All patients who were admitted to acute inpatient rehabilitation from September 5, 2018, to February 7, 2020, met the inclusion criteria, and completed two surveys (assessing continuity of care and functional safety concerns) upon discharge and 1 month after discharge were included in the study. RESULTS: A total of 198 patients completed the study, and no major concerns were reported by the patients. The greatest concern was a lack of adequate communication management among different providers, reported by only 10 (5.0%) patients. The combined fall and near-fall rate within 1 month after discharge was (25/198) 13%. Brain metastasis, a comorbidity of depression, and a history of falls were significantly associated with a higher risk of falls or near falls within 1 month after discharge. CONCLUSION: Although overall patients with cancer reported adequate continuity of care and feeling safe to function at home after acute inpatient rehabilitation, it is important to be aware that fall or near-fall events within 1 month after acute inpatient rehabilitation are associated with brain metastasis, comorbidity of depression, and a history of falls. Thus, patients with these risk factors may benefit from including more focused fall prevention education and interventions. IMPLICATIONS FOR PRACTICE: Patients with cancer often have extensive problems that require care from multiple health care providers simultaneously, and a high level of coordination is needed for adequate transition of care from the inpatient to the outpatient setting. This transition of care period is prone to inadequate continuity of care and, for older adults, a particular risk for falls. Assessment for risk of fall is also an important factor to consider when evaluating patients to continue oncology treatments. There is a gap in knowledge regarding patient-reported continuity of care and functional safety concerns after acute inpatient cancer rehabilitation.

Frequency of Sarcopenia, Sarcopenic Obesity, and Changes in Physical Function in Surgical Oncology Patients Referred for Prehabilitation.

PURPOSE: Sarcopenia and suboptimal performance status are associated with postoperative complications and morbidity in cancer patients. Prehabilitation has emerged as an approach to improve fitness and muscle strength in patients preoperatively. We sought to describe the frequency of sarcopenia and sarcopenic obesity (SO) in a cohort of cancer patients referred for prehabilitation and the association between body composition and physical function. METHODS: In this retrospective review of 99 consecutive cancer patients referred for prehabilitation prior to intended oncologic surgery, prehabilitation included physical medicine and rehabilitation (PM&R) physician evaluation of function and physical therapy for individualized home-based exercise. Sarcopenic A was defined using sex-adjusted norms of skeletal muscle (SKM), measured using the sliceOmatic software (TomoVision, 2012) on computed tomography images at baseline. Sarcopenic B was defined by abnormal SKM and physical function. SO was defined as sarcopenia with BMI ≥ 25. Six-minute walk test (6MWT), 5 times sit-to-stand (5×STS), and grip strength were obtained at consultation (baseline) and at preoperative follow-up (if available). RESULTS: Forty-nine patients (49%) were Sarcopenic A, 28 (28%) SO, and 38 (38%) Sarcopenic B. Age was negatively correlated with SKM (P = .0436). There were no significant associations between Sarcopenic A/B or SO with baseline or changes in physical function. Assessed by sex, Sarcopenic A females had low 5×STS (P = .04) and Sarcopenic B females had low GS (P = .037). Sarcopenic B males had low preoperative GS (P = .026). 6MWT and grip strength at baseline were lower than age- and sex-related norms (both P < .001). Preoperatively, 6MWT distance and 5×STS time improved (both P < .001). Functional improvement in the sarcopenic and nonsarcopenic patients did not differ according to sex. CONCLUSIONS: In this cohort of prehabilitation surgical oncology patients, frequencies of sarcopenia and SO were high, and baseline physical function was abnormal but improved significantly regardless of body composition. These findings suggest that patients have considerable prehabilitation needs and are capable of improving with comprehensive care.

Association between Spirituality, Religiosity, Spiritual Pain, Symptom Distress, and Quality of Life among Latin American Patients with Advanced Cancer: A Multicenter Study.

Objectives: The purpose of this multicenter study was to characterize the association between spirituality, religiosity, spiritual pain, symptom distress, coping, and quality of life (QOL) among Latin American advanced cancer patients. Methods: Three hundred twenty-five advanced cancer patients from palliative care clinics in Chile, Guatemala, and the United States completed validated assessments: Faith, Importance and Influence, Community, and Address (FICA) (spirituality/religiosity), Edmonton Symptom Assessment Scale-Financial/Spiritual (ESAS-FS), including spiritual pain, Penn State Worry Questionnaire-Abbreviated (PSWQ-A), Center for Epidemiologic Studies Depression Scale (CES-D), Brief-coping strategies (COPE) and Brief religious coping (RCOPE) and RCOPE, respectively, and Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, Expanded version (FACIT-Sp-Ex). Results: Median age: 58 years (range: 19-85); 60% female; and 62% Catholic and 30% Christian, but not Catholic. Three hundred fifteen patients (97%) considered themselves spiritual and 89% religious, with median intensities of 7 (interquartile range [IQR]: 5-10) and 7 (5-9), respectively (0-10 scale, 10 = "very much"). Median importance of spirituality/religiosity was 10 (IQR: 8-10). The frequency and associations between spirituality/religiosity and various items were as follows: helps to cope with illness (98%; r = 0.66303; p < 0.0001), positive effect on physical symptoms (81%; r = 0.42067; p < 0.0001), and emotional symptoms (84%; r = 0.16577; p < 0.0001). One hundred ninety-five patients (60%) reported that their spiritual/religious needs had not been supported by the medical team. Spiritual pain was reported in 162/311 patients (52%), with median intensity of 6 (IQR: 5-8). Spiritual pain was associated with pain (p = 0.0225), depression (p < 0.0001), anxiety (p < 0.0001), worry (p < 0.001), behavioral disengagement (p = 0.0148), FACIT-Sp-Ex score (p = 0.0002), and negative RCOPE (p < 0.0001). Significance of Results: Spirituality and religiosity are frequent, intense, and rarely addressed among Latin American patients. Spirituality/religiosity was associated with positive COPE and higher QOL. Spiritual pain was also frequent and associated with physical and psychosocial distress. These patients need increased spiritual/religious support.

Exercise Barriers and Adherence to Recommendations in Patients With Cancer.

PURPOSE: The American College of Sports Medicine exercise guidelines for cancer survivors encourage a combination of 150 minutes of moderate-intensity aerobic activity and 2-3 weekly sessions of strength training. Cancer survivors often experience more barriers to meeting recommended guidelines because of side effects from cancer treatments. Our aim was to measure the cancer survivors' adherence and barriers with these recommendations. METHODS: Two hundred adult cancer survivors completed surveys (Stanford Patient Education Research Center Exercise Behaviors Survey and an exercise barrier scale) reporting their physical activity, barriers to physical activity, and symptom assessment. RESULTS: A total of 68/200 participants (34%) reported adhering to the recommended physical activity guidelines of 150 minutes or more per week. Those who adhered to the guidelines reported fewer barriers to exercise (mean of 2.44 compared with 4.15 barriers, P < .0001). Female participants (P = .01), higher number of barriers, and feeling of poor well-being were less likely to report at least 60 or 150 minutes of exercise time. Lack of interest (P = .003) and self-discipline (P = .001) were reported as barriers. These participants were more likely to report high symptom burden of pain (P = .007) and fatigue (P = .005). Participants who reported < 60 minutes of exercise reported lack of enjoyment (P = .03), lack of equipment (P = .01), and symptoms of poor appetite, poor well-being, and increased dyspnea. CONCLUSION: Although recommendations are given for exercise, adherence to recommendations is low. Issues of motivation, including lack of interest and self-discipline, and symptoms of pain and fatigue were some of the main reported barriers to adhering to the recommended exercise guidelines. Therefore, interventions aimed at increasing motivation and treating symptoms could improve cancer survivor adherence to recommended exercise guidelines.

A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma.

BACKGROUND: To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). METHODS: Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). RESULTS: A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). CONCLUSIONS: In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

STK11/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition.

PURPOSE: Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes. EXPERIMENTAL DESIGN: We conducted a retrospective analysis of 194 patients with stage I-III NSCLC, including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain. RESULTS: In stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P = 0.0108), and shorter DFS (HR 2.530, P = 0.0029) and OS (HR 2.198, P = 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy. CONCLUSIONS: These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.

The development of a nomogram to determine the frequency of elevated risk for non-medical opioid use in cancer patients.

OBJECTIVE: Non-medical opioid use (NMOU) is a growing crisis. Cancer patients at elevated risk of NMOU (+risk) are frequently underdiagnosed. The aim of this paper was to develop a nomogram to predict the probability of +risk among cancer patients receiving outpatient supportive care consultation at a comprehensive cancer center. METHOD: 3,588 consecutive patients referred to a supportive care clinic were reviewed. All patients had a diagnosis of cancer and were on opioids for pain. All patients were assessed using the Edmonton Symptom Assessment Scale (ESAS), Screener and Opioid Assessment for Patients with Pain (SOAPP-14), and CAGE-AID (Cut Down-Annoyed-Guilty-Eye Opener) questionnaires. "+risk" was defined as an SOAPP-14 score of ≥7. A nomogram was devised based on the risk factors determined by the multivariate logistic regression model to estimate the probability of +risk. RESULTS: 731/3,588 consults were +risk. +risk was significantly associated with gender, race, marital status, smoking status, depression, anxiety, financial distress, MEDD (morphine equivalent daily dose), and CAGE-AID score. The C-index was 0.8. A nomogram was developed and can be accessed at https://is.gd/soappnomogram. For example, for a male Hispanic patient, married, never smoked, with ESAS scores for depression = 3, anxiety = 3, financial distress = 7, a CAGE score of 0, and an MEDD score of 20, the total score is 9 + 9+0 + 0+6 + 10 + 23 + 0+1 = 58. A nomogram score of 58 indicates the probability of +risk of 0.1. SIGNIFICANCE OF RESULTS: We established a practical nomogram to assess the +risk. The application of a nomogram based on routinely collected clinical data can help clinicians establish patients with +risk and positively impact care planning.

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

OBJECTIVE: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. DESIGN: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). RESULTS: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. CONCLUSIONS: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. TRIAL REGISTRATION NUMBER: gov Identifier: NCT02052908.

Random urine drug testing among patients receiving opioid therapy for cancer pain.

BACKGROUND: There is limited information regarding the true frequency of nonmedical opioid use (NMOU) among patients receiving opioid therapy for cancer pain. Data to guide patient selection for urine drug testing (UDT) as well as the timing and frequency of ordering UDT are insufficient. This study examined the frequency of abnormal UDT among patients with cancer who underwent random UDT and their characteristics. METHODS: Demographic and clinical information for patients with cancer who underwent random UDT were retrospectively reviewed and compared with a historical cohort that underwent targeted UDT. Random UDT was ordered regardless of a patient's risk potential for NMOU. Targeted UDT was ordered on the basis of a physician's estimation of a patient's risk for NMOU. RESULTS: In all, 552 of 573 eligible patients (96%) underwent random UDT. Among these patients, 130 (24%) had 1 or more abnormal results; 38 of the 88 patients (43%) who underwent targeted UDT had 1 or more abnormal results. When marijuana was excluded, 15% of the random group and 37% of the targeted group had abnormal UDT findings (P < .001). It took a shorter time from the initial consultation to detect 1 or more abnormalities with the random test than the targeted test (median, 130 vs 274 days; P = .02). Abnormal random UDT was independently associated with younger age (P < .0001), male sex (P = .03), Cut Down, Annoyed, Guilty, and Eye Opener-Adapted to Include Drugs positivity (P = .001), and higher Edmonton Symptom Assessment System anxiety (P = .01). CONCLUSIONS: Approximately 1 in 4 patients receiving opioids for cancer pain at a supportive care clinic who underwent random UDT had 1 or more abnormalities. Random UDT detected abnormalities earlier than the targeted test. These findings suggest that random UDT is justified among patients with cancer pain.

CoxPhLb: An R Package for Analyzing Length Biased Data under Cox Model.

Data subject to length-biased sampling are frequently encountered in various applications including prevalent cohort studies and are considered as a special case of left-truncated data under the stationarity assumption. Many semiparametric regression methods have been proposed for length-biased data to model the association between covariates and the survival outcome of interest. In this paper, we present a brief review of the statistical methodologies established for the analysis of length-biased data under the Cox model, which is the most commonly adopted semiparametric model, and introduce an R package CoxPhLb that implements these methods. Specifically, the package includes features such as fitting the Cox model to explore covariate effects on survival times and checking the proportional hazards model assumptions and the stationarity assumption. We illustrate usage of the package with a simulated data example and a real dataset, the Channing House data, which are publicly available.

Biomarker Modulation Study of Celecoxib for Chemoprevention in Women at Increased Risk for Breast Cancer: A Phase II Pilot Study.

In preclinical studies, celecoxib has been associated with reduced risk of breast cancer. In this study, the aim was to assess the biomodulatory effect of celecoxib on blood and benign breast tissue biomarkers in women at increased risk for breast cancer. Women at increased risk for breast cancer [5-year Gail risk score of >1.67%, history of atypical hyperplasia, lobular carcinoma in situ, or previous estrogen receptor (ER)-negative breast cancer] were treated with celecoxib at 400 mg orally twice daily for 6 months. Participants underwent random periareolar fine needle aspiration and blood draw at baseline and at 6 months for analysis of biomarkers: serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3; tissue expression of Ki-67 and ER; as well as cytology. Forty-nine patients were eligible for analysis. Median IGFBP-1 levels increased significantly from 6.05 ng/mL at baseline to 6.93 ng/mL at 6 months (P = 0.04), and median IGFBP-3 levels decreased significantly from 3,593 ng/mL to 3,420 ng/mL (P = 0.01). We also detected favorable changes in cytology of 52% of tested sites after 6 months of celecoxib therapy. No changes in tissue Ki-67 and ER expression levels were observed. No grade 3 or 4 toxicity was recorded. Celecoxib was well tolerated and induced favorable changes in serum biomarkers as well as cytology in this pilot phase II trial. A phase IIb placebo-controlled study with celecoxib could be considered for women at increased risk for breast cancer.

EpCAM-independent isolation of circulating tumor cells with epithelial-to-mesenchymal transition and cancer stem cell phenotypes using ApoStream® in patients with breast cancer treated with primary systemic therapy.

BACKGROUND: Tumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR). METHODS: Blood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (ß-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low). RESULTS: We enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated. CONCLUSIONS: ApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted.