Phosphorylated transducer and activator of transcription-3 (pSTAT3) immunohistochemical expression in paired primary and metastatic colorectal cancer.

BACKGROUND: Signal Transducer and Activator of Transcription-3 (STAT3) mediates cellular functions. We assessed the IHC expression of phosphorylated STAT3 (pSTAT3) in paired primary tumors and liver metastases in patients with advanced stage colorectal cancer (CRC). METHODS: We included patients with tissue blocks available from both the primary CRC and a surgically resected liver metastasis. The IHC pSTAT3 expression agreement was measured using Cohen's kappa statistic. RESULTS: The study included 103 patients, 55% male, median age was 64. 43% tumors originated in rectum, and 63% of the primary tumors were synchronous. Expression of pSTAT3 was 76% in liver metastases and 71% in primary tumors. A difference in pSTAT3 staining between the primary tumor and liver metastases was noted in 64%. There was lost expression of pSTAT3 in the liver metastases in 28% and gained expression in 36% of cases compared to the primary. The kappa statistic comparing agreement between staining patterns of the primary tumors and liver metastases was a "less-than-chance", at -0.02. Median survival was 4.9 years, with no difference in survival outcomes by pSTAT3 expression in the primary tumor or liver metastases. DISCUSSION: STAT3 is not a prognostic marker in the selective setting of metastatic CRC to liver, but it may remain a potential therapeutic target given most liver metastases expressed pSTAT3. Discordant pSTAT3 expression in between primary tumors and paired liver metastases suggests that use of this class of drug to treat liver predominant metastatic colorectal cancer in a biomarker-driven approach may require confirmatory liver tumor biopsy.

Downstream consequences of abnormal cognitive screening in older adults seen pretreatment in a geriatric oncology clinic.

INTRODUCTION: Although screening for cognitive impairment (CI) is an important part of a comprehensive geriatric assessment (CGA), little is known about the downstream work-up of abnormal screening or its impact on cancer treatment. We characterized the downstream workup in diagnosing CI and its impact on cancer treatment decision-making. METHODS: Patients who underwent a pre-treatment CGA at an academic Geriatric Oncology (GO) clinic between July 2015 and June 2018 and had a positive Mini-Cog (≤ 3 out of 5) screen were included. Data were collected from medical charts and database review. Analyses were primarily descriptive. RESULTS: Of 82 patients seen in the pre-treatment setting, 46 (56.1%) had a positive Mini-Cog screen. Of those, 12 (26.1%) were diagnosed with dementia, 8 (17.4%) were diagnosed with mild cognitive impairment and 10 (21.7%) had CI not otherwise specified. Although 46 patients had a positive screen, only 30 patients (65.2%) were classified as cognitively "abnormal" in the GO team final assessment. Change to oncologic treatment due to CI was seen in 12 (40.0%) cases. Increased delirium risk was identified in 9 (75.0%) of 12 surgical cases; however, delirium prevention was only recommended in 5 cases (55.6%). Strategies to optimize patients with CI included targeting falls prevention (n = 13), home/personal safety (n = 7), medication safety (n = 7), and nutrition (n = 6). Pharmacotherapy for cognition was not recommended in any case. CONCLUSION: Undiagnosed CI is prevalent in the GO setting and influenced treatment in 40.0% of cases. Gaps were identified in clinician and patient/caregiver education around delirium risk. Addressing these issues may improve patient care.

Performance of the Vulnerable Elders Survey 13 screening tool in identifying cancer treatment modification after geriatric assessment in pre-treatment patients: A retrospective analysis.

PURPOSE: Geriatric assessment (GA) is recommended for older adults ≥ 70 years with cancer to guide treatment selection. Screening tools such as the Vulnerable Elders Survey (VES-13) and G6 have been used to identify patients at highest need of GA. Whether either tool predicts a change in oncologic treatment following GA is unclear. METHODS: Patients attending a geriatric oncology clinic between July 2015 and June 2017 who completed a VES-13 and underwent subsequent GA were included. Clinical information was extracted from a prospectively maintained database. G6 scores were assigned retrospectively. Patients were stratified into those who were "VES-13 positive" (score ≥ 3) and "VES-13 negative" (score < 3). Logistic regression was used to explore the relationship between VES-13 score, G6 score, and treatment modification. RESULTS: Ninety-nine patients were seen prior to initiating cancer treatment. The median VES-13 score was 7; with 81.8% of patients scoring ≥3. The treatment plan was modified in 47.5% of patients after GA. VES-13 score was predictive of treatment plan modification (63.0% among VES-13 positive versus 16.7% among VES-13 negative patients; p = 0.001). G6 performed similarly to the VES-13. The only statistically significant predictor of treatment change in multivariable analysis was performance status. CONCLUSION: VES-13 positive patients are more likely to undergo treatment modification to reduce treatment intensity or supportive care only. The VES-13 may provide oncologists with a rapid, reliable way of identifying vulnerability in older adults with cancer who may need further GA prior to commencing cancer treatment.

Exploring the geriatric needs of oncology inpatients at an academic cancer centre.

PURPOSE: Geriatric Assessments (GAs) in older adults with cancer have informed treatment decision-making and refined survival prediction. However, little is known about the needs of older inpatients with cancer. Our objectives were to test the feasibility of a bedside GA, assess the prevalence of impairments in geriatric domains, determine how many were unknown to the medical team, and assess the impact of GA on patient care. METHODS: We conducted a cross-sectional observational single-centre pilot study. Structured GAs were performed on patients age 65+ admitted to the medical or radiation oncology inpatient wards at a tertiary care cancer centre. GA findings were shared with the patient's most responsible physician (MRP). RESULTS: 356 patients were screened, 39 were eligible and approached, and 37 were enrolled (recruitment rate 95%). Completion of the GA was possible in 92% of patients (34/37) and required a mean of 35 min. The mean number of geriatric domains impaired per patient was five (of seven assessed domains). The most common abnormal domains not known to the medical team were medication optimization (91%), cognition (90%), mood (69%), and social vulnerability (69%). MRPs responded to our survey for fifteen of thirty-three participants (45% response rate), and indicated that the GA results provided helpful information for patient management in 10 of 15 cases. CONCLUSION: Abnormal geriatric domains are common in older inpatients with cancer. Domains such as medication optimization, cognition, mood, and social vulnerability often go undetected and unaddressed. Identifying abnormal domains may improve the care of older inpatients with cancer.

Prognostic and predictive clinical factors in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel.

INTRODUCTION: Cabazitaxel is one of several treatment options available for patients with metastatic castration-resistant prostate cancer who have progressed on docetaxel. Little is known about clinical factors that influence prognosis or treatment response for patients receiving cabazitaxel. Identifying prognostic and predictive factors could contribute to the optimal selection of patients for treatment after docetaxel. METHODS: A retrospective review of patients enrolled on the cabazitaxel Canadian Early Access Program (C-EAP) was performed. Clinical factors were analyzed by univariable and multivariable Cox proportional hazards and logistic regression analysis to identify independent predictors of prognosis and response. RESULTS: Forty-five patients from five centres in Canada were included in this study. On multivariable analysis, lower hemoglobin was associated with shorter survival. No other factors were independently associated with survival, prostate-specific antigen (PSA) response, or primary PSA progression. CONCLUSIONS: Clinical factors predicting survival or treatment response were not identified for men with castration-resistant prostate cancer receiving cabazitaxel. Larger studies may be necessary to identify clinical factors and biomarkers that identify whether patients should or should not receive cabazitaxel.

Beyond the black box of geriatric assessment: Understanding enhancements to care by the geriatric oncology clinic.

OBJECTIVE: Comprehensive geriatric assessment (CGA) of older adults with cancer aids treatment decision-making and prognostication. Much less is known about the supportive care elements or enhancements to care afforded by the CGA. We characterized the enhancements to care provided by a geriatric oncology clinic and determined how these vary by indication for referral. MATERIALS AND METHODS: All patients age 65 or older referred to a single academic geriatric oncology clinic between July 2015 (clinic opening) and June 2017 were included. Treatment enhancements were prospectively recorded in 5 categories: educational support, comorbidity management, symptom management, oncologic treatment delivery, and peri-operative management recommendations. Indications for referral were categorized into 3 groups: pre-treatment (n = 97, 44%), on active treatment (n = 89, 41%), and survivorship phase (n = 33, 15%). Data were analyzed using descriptive statistics and multivariable logistic regression. RESULTS: 219 patients were seen during the study period (mean age 79.7 years, 69% male). Overall, educational support (96%) and comorbidity management (95%) were the most common enhancements, whereas peri-operative management (10%) was the least common and provided only to pre-treatment patients. Enhancements to cancer treatment delivery were offered more often to patients pre-treatment than on active treatment (61% versus 41%, p < 0.001). Other enhancements to care did not vary by indication for referral. CONCLUSION: Educational support and comorbidity management are nearly universally offered. Most enhancements to care do not vary by indication for referral. Understanding the enhancements to care provided by geriatric oncology clinics can help with resource planning and program design.

Geriatric oncology screening tools for CGA-based interventions: results from a phase II study of geriatric assessment and management for older adults with cancer.

INTRODUCTION: Screening tools in geriatric oncology have traditionally been studied for their ability to identify patients who have abnormal domains on a comprehensive geriatric assessment (CGA). However, an alternative outcome of identifying patients who would receive CGA-based interventions could improve selection of patients whose management will be altered by a CGA. The objective of this study was to assess the performance of three geriatric oncology screening tools for their ability to predict for CGA-based interventions. MATERIALS AND METHODS: G8, Vulnerable Elders Survey (VES-13) and a modified frailty phenotype (mFP) screening tools were collected prospectively for patients enrolled in a phase II trial of geriatric evaluation and management. Interventions were defined as a new clinical diagnosis, change in management of a comorbidity, or referral to an allied health professional. Performance characteristics were calculated for each screening tool based on the outcomes of ≥2 abnormal CGA-domains and ≥1 CGA-based interventions. RESULTS: Discordance between the outcomes was seen in 31.9% of patients. Using the outcome of ≥2 abnormal CGA-domains, the G8 was most sensitive at 0.73 while VES-13 and mFP were both 1.0 specific. Using the outcome of CGA-based interventions the most sensitive tool was still the G8 at 0.64 and the most specific was the mFP at 0.80. DISCUSSION: All screening tests' performance characteristics for the G8, VES-13 and mFP were lower for the outcome of CGA-based interventions than for the traditional outcome of abnormal CGA-domains. Significant discordance between the outcomes highlights the difficulty with trying to predict which patients will truly benefit from a CGA.

Radical Treatment of Stage II Non-small-cell Lung Cancer With Nonsurgical Approaches: A Multi-institution Report of Outcomes.

INTRODUCTION: Standard management of stage II non-small-cell lung cancer (NSCLC) is surgery, often followed by adjuvant chemotherapy. However, some patients do not undergo surgery for various reasons. We examined outcomes in this defined patient group. METHODS: We reviewed the records of patients with stage II NSCLC treated nonsurgically with curative intent from 2002 to 2012 across 3 academic cancer centers. Data collected included demographics, comorbidities, staging, treatments, and survival. The primary endpoint was overall survival (OS). We assessed factors associated with treatment choice and OS. RESULTS: A total of 158 patients were included: the median age was 74 years (range, 50-91 years), 44% were female, and 68% had a performance status of 0 to 1. The stage II groupings of the patients were T2b-T3 N0 in 55% and N1 in 45%. The most common reasons for inoperability were inadequate pulmonary reserve (27%) and medical comorbidities (24%). All patients received radical radiotherapy (RT) (median, 60 Gy [range, 48-75 Gy]). Seventy-three percent received RT alone; 24% received concurrent and 3% sequential chemoradiotherapy (CRT). In multivariate analyses, CRT was less likely in older patients (≥ 70 years) (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11-0.70; P = .006) and in patients with higher (> 5) Charlson comorbidity scores (OR, 0.34; 95% CI, 0.13-0.90; P = .03) or normal (< 10 × 109/L) white blood cell counts (OR, 0.26; 95% CI, 0.09-0.73; P = .01). At the time of our analysis, 74% have died. The median OS was 22.9 months (range, 17.1-26.6 months). Patients who had undergone CRT had a significantly longer median OS than those receiving RT alone (39.1 vs. 20.5 months; P = .0019), confirmed in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21-0.69; P = .001). CONCLUSION: Nonsurgical approaches to management of stage II NSCLC are varied. Treatment with CRT was associated with significantly longer survival compared with RT alone. A randomized trial may be warranted.

Disruption of the Y-box binding protein-1 results in suppression of the epidermal growth factor receptor and HER-2.

The overexpression of the epidermal growth factor receptor (EGFR) and HER-2 underpin the growth of aggressive breast cancer; still, it is unclear what governs the regulation of these receptors. Our laboratories recently determined that the Y-box binding protein-1 (YB-1), an oncogenic transcription/translation factor, induced breast tumor cell growth in monolayer and in soft agar. Importantly, mutating YB-1 at Ser(102), which resides in the DNA-binding domain, prevented growth induction. We reasoned that the underlying cause for growth attenuation by YB-1(Ser(102)) is through the regulation of EGFR and/or HER-2. The initial link between YB-1 and these receptors was sought by screening primary tumor tissue microarrays. We determined that YB-1 (n = 389 cases) was positively associated with EGFR (P < 0.001, r = 0.213), HER-2 (P = 0.008, r = 0.157), and Ki67 (P < 0.0002, r = 0.219). It was inversely linked to the estrogen receptor (P < 0.001, r = -0.291). Overexpression of YB-1 in a breast cancer cell line increased HER-2 and EGFR. Alternatively, mutation of YB-1 at Ser(102) > Ala(102) prevented the induction of these receptors and rendered the cells less responsive to EGF. The mutant YB-1 protein was also unable to optimally bind to the EGFR and HER-2 promoters based on chromatin immunoprecipitation. Furthermore, knocking down YB-1 with small interfering RNA suppressed the expression of EGFR and HER-2. This was coupled with a decrease in tumor cell growth. In conclusion, YB-1(Ser(102)) is a point of molecular vulnerability for maintaining the expression of EGFR and HER-2. Targeting YB-1 or more specifically YB-1(Ser(102)) are novel approaches to inhibiting the expression of these receptors to ultimately suppress tumor cell growth.