Class III β-tubulin expression as a predictor of docetaxel-resistance in metastatic castration-resistant prostate cancer

About half of the patients treated with docetaxel in the setting of metastatic castration-resistant prostate cancer (CRPC) are non-responders. Therefore, a marker of response would be beneficial for clinical decision-making. We evaluated class III β-tubulin (βIII-tubulin) expression as a predictor of resistance in this setting, which previously has been correlated with lack of response to taxanes in other cancers. Patients with CRPC were included if they were treated with at least 3 cycles of docetaxel between 1990 and 2011. βIII-tubulin expression was assessed by immunostaining, which was performed in tissue samples obtained either via biopsy or prostatectomy at the time of diagnosis. Rates of prostate-specific antigen (PSA) response and overall survival (OS) following docetaxel treatment were compared between patients with high (2+ or 3+ staining) vs. low (0 or 1+ staining) βIII-tubulin expression. Of 73 patients, 26 (35%) had a high expression of βIII-tubulin. A PSA decline of 10% or greater occurred in 65% of patients with a high βIII-tubulin expression vs. 89% with a low βIII-tubulin expression (p = 0.0267). The median OS for patients with a high βIII-tubulin expression was 17.4 (95% CI 8.7-21.0) months vs. 19.8 (95% CI 16.6-23.6) months for patients with a low expression (p = 0.039). Our results show that a high βIII-tubulin expression is a negative prognostic factor in metastatic CRPC patients treated with docetaxel

Cetuximab and anemia prevention in head and neck cancer patients undergoing radiotherapy

BACKGROUND: Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia. METHODS: We queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared. RESULTS: A total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p \u3c 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068). CONCLUSIONS: In contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia

Molecular features and race-associated outcomes of SPOP-mutant metastatic castration-resistant prostate cancer

BACKGROUND: Inactivating alterations in SPOP frequently occur in prostate cancer and promote increased dependency on androgen receptor (AR)-mediated oncogenic signaling. The presence of SPOP mutation (SPOP-mutant [SPOP-mut]) may therefore impact therapeutic outcomes with AR-directed therapies and docetaxel in metastatic castration-resistant (mCRPC). METHODS: This was a retrospective study of mCRPC patients treated at an urban academic hospital (n = 103). Patients underwent tumor DNA sequencing to determine SPOP mutational status (SPOP-mut). Outcomes measured were overall survival (OS) from diagnosis and treatment with second-generation AR signaling inhibitor (ARSI) or docetaxel and time to PSA progression (prostate-specific antigen-progression-free survival [PSA-PFS]) compared by SPOP status using Kaplan-Meier curves and log-rank test. The univariable and multivariable Cox proportional hazard model evaluated the association of SPOP mutation and outcomes adjusted for clinicopathologic features. RESULTS: SPOP-mut was associated with longer PSA-PFS in mCRPC (median 1.79 vs. 0.84 years; p = 0.06) and multivariate analysis (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.17-0.84; p = 0.02). SPOP-mut demonstrated a higher median PSA decline compared to SPOP wild-type (median decline 100% vs. 92%, p = 0.02). SPOP-mut was not associated with OS from the start of ARSI or docetaxel (median OS not reached vs. 2.0 years) or PSA-PFS on docetaxel (median PSA-PFS 0.4 vs. 0.5 years) in mCRPC. The majority of SPOP mutations were identified in African American (AA) patients (69.2%) compared to Caucasian patients (30.8%). Race-associated multivariate analysis revealed no significant differences in OS from the start of ARSI or the start of docetaxel and no differences in ARSI or docetaxel PSA-PFS between AA and Caucasian patients. Molecular profiling demonstrated that AA patients had a higher frequency of SPOP mutations and greater heterogeneity of SPOP variants within the coding sequence. Analysis of concurrent genomic alterations revealed that SPOP mutations co-occur with APC mutations (p = 0.001) and alterations in the Wnt pathway (p = 0.017). CONCLUSIONS: Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race-associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker-directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients

Real-world effectiveness of the pegfilgrastim on-body injector in preventing severe neutropenia

INTRODUCTION: Granulocyte colony-stimulating factors are used in medical oncology for the prevention of neutropenia. On-body injectors (OBI) have an advantage over the traditional injection (TI) method of not requiring a second visit to the clinic, but these devices are subject to failure. The objective of this study was to assess the efficacy of OBIs in the real-world. METHODS: Women with breast cancer diagnosed between June 2015 and June 2016 treated with cytotoxic chemotherapy and a granulocyte colony-stimulating factor were retrospectively identified from the medical records of Henry Ford Hospital. The primary outcome was the incidence of severe neutropenia (SN), defined as an absolute neutrophil count (ANC) ≤500. Secondary outcomes included incidence of neutropenia (ANC ≤ 1500), neutropenic fever, and mortality. A secondary analysis of the data was performed to identify predictors of SN. RESULTS: A total of 837 cycles of chemotherapy were analyzed. The OBI was used in 395 cycles and the TI in 442. The OBI group had patients that were older, had higher baseline ANC, and were more often white. The incidences of SN, neutropenic fever and neutropenia were not different between groups. Patients with a lower baseline ANC and white ethnicity were at a higher risk for SN. AC (doxorubicin and cyclophosphamide) was the most commonly used chemotherapy regimen (38% of total cycles). CONCLUSIONS: There was no difference in the efficacy of the OBI and TI methods for preventing SN, neutropenic fever and neutropenia

Acute Heart Failure Exacerbation and Influenza Infection

Background: Influenza infection causes 3-5 million cases of severe illness annually and has been linked to exacerbations of congestive heart failure (CHF) as well as myocarditis. Patients with diagnosed CHF appear to have an increased risk of hospitalization during influenza season, but a relationship between serologically diagnosed influenza infection and acute heart failure (AHF) exacerbations has not been studied. Methods: This was a retrospective chart review studying patients with a diagnosis of CHF between April and October 2016 with specific focus on those presenting with AHF exacerbations until 2018. Descriptive data was collected regarding patient demographics, total number and dates of encounters, length of stay, presenting laboratory values, influenza testing Results, intensive care admission, and outcomes including mortality. This data was divided based on influenza testing status and univariate analysis was applied to capture any association of peak influenza infection with peak AHF encounters, correlation of influenza infection with length of stay, and correlation of influenza infection with patient demographics. Descriptive statistics were gathered on all variables of interest. Statistical significance was set at p-value \u3c 0.05. All analyses were performed using SAS 9.4. Results: Out of 1880 patients with a diagnosis of AHF exacerbation, there were two defined groups: influenza positive (n=28), and influenza negative/not tested (n=1852). There was no significance noted amongst the rate of heart failure exacerbations between these two groups (Table 1, p-value 0.134). Out of all variables analyzed, only two demonstrated statistical significance between influenza positive and influenza negative/not tested groups. Diagnosis of pulmonary hypertension (p-value 0.013) and coronary artery disease (p = 0.031) was more likely in influenza positive patients. No statistically significant correlation was found for the primary endpoint of influenza positivity with acute heart failure exacerbation. Conclusions: This data comprised a significant portion of patients with AHF exacerbations with negative influenza tests or those that were not tested. This allows us to deduce that perhaps a larger cohort of patients may be required to determine if there is true statistical significance of additional variables and endpoints. These Results also indicate a need for higher clinical suspicion of influenza infection in patients with heart disease, particularly coronary artery disease and pulmonary hypertension. Future studies may also focus on the effect of influenza treatment on hospital outcomes for cardiac patients

Does Cetuximab Reduce the Risk of Anemia in Patients Undergoing Radiation Therapy for Head and Neck Cancers?

Purpose/Objective(s): Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels promote RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, resulted in significantly lower rates of RT induced anemia for locally advanced head and neck squamous cell carcinoma (HNSCC) patients receiving definitive RT vs RT-alone according to Bonner et al; and other studies compared to concomitant chemotherapy. However, little is known for cases receiving cetuximab with RT in the adjuvant setting. Materials/Methods: We queried our institutional HNSCC database for surgically staged non-metastatic cases that received adjuvant RT with or without concomitant cetuximab between 2006-2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. All included patients need to have at least one complete blood count pre- and post-RT end. We compared RT-cetuximab vs RT-alone for prevalence of baseline and post-RT anemia, defined as Hb below 12g/dL in females and 13g/dL in males, and mean hemoglobin (Hb) levels. We also assessed the improvement in Hb level post-RT (resolution of baseline anemia or Hb increase of at least 1g/dL above baseline), in addition to overall survival (OS) in relation to anemia/Hb dynamics. Results: We were able to identify 66 patients who fit our inclusion criteria, of which 27 (41%) received RT-cetuximab, with the remaining receiving RT-alone (n=39, 59%). Median age was 62.5 years (range, 34-88 years), males 80%, black 29%, and 85% had a smoking history. The majority of cases (73%) were locally advanced. Oral cavity and oropharynx were the most common subsites (37.5% each), with HPV+ve cases representing 52% of the later. The study groups were well-balanced, except for higher rates of positive final surgical margins, and extracapsular space invasion and median RT dose (p\u3c0.05). Baseline anemia was diagnosed in 70.4% in RT-cetuximab vs 76.9% in the RT-alone, p=0.76; with similar mean Hb level (11.7g/dL in both). Meanwhile, baseline iron, vitamin-B12 and folate deficiencies, and chronic kidney disease were non-different. After completion of RT, mean Hb was significantly higher in the RT-alone (12.9±1.4 g/dL) compared to RT-Cetuximab (11.9±2.1 g/dL), p=0.02. Nevertheless, higher anemia levels (70% vs 51%) and lower improvement of Hb post-RT (81.5% vs 92.3%) were both non-significant for RT-cetuximab vs RT-alone respectively, p\u3e0.05 for both. On multivariate analysis, baseline anemia was associated with worse OS (p=0.0052), unlike improvement of Hb post-RT (p=0.14) with a corresponding better improvement of Hb (56.4% vs. 25.9%, p=0.014), albeit lower anemia levels (70% vs. 51%), was non significant (p=0.195). On multivariate analysis, lack of baseline anemia was associated with better OS (p=0.0052), whereas improvement of Hb post-RT was only marginal (p=0.068). Conclusion: In a homogenous cohort of HNSCC patients treated postoperatively, concomitant cetuximab was not associated with lower RT-induced anemia, in contrast to previous studies