Geographic Origin may Affect Outcomes for Hispanic Patients with Non-Small Cell Lung Cancer in the United States.

BACKGROUND: Social determinants of health thoroughly explored in the literature include insurance status, race, and ethnicity. There are over 50 million self-identifying Hispanics in the United States. This, however, represents a heterogeneous population. We used a national registry to investigate for significant differences in outcomes of Hispanic patients with non-small cell lung cancer (NSCLC) in the Unites states, by geographic region of origin. MATERIALS AND METHODS: We identified a cohort of Hispanic patients in the Unites states with NSCLC for which region of origin was documented within the 2004 to 2016 National Cancer Database (NCDB) registry. This included patients from Cuba, Puerto Rico, Mexico, South and Central America, and the Dominican Republic. We performed multivariate logistic regression modeling to determine whether origin was a significant predictor of cancer staging at diagnosis, adjusting for age, sex, histology, grade, insurance status, and facility type. Race was not included due to a nonsignificant association with stage at diagnosis at the bivariate level in this cohort. Subsequently, we used Kaplan-Meier modeling to identify whether overall survival (OS) of Hispanic patients differed by origin. RESULTS: A total of 12,557 Hispanic patients with NSCLC were included in this analysis. The breakdown by origin was as follows: n = 2071 (16.5%) Cuban, n = 2360 (18.8%) Puerto Rican, n = 4950 (39.4%) Mexican, n = 2329 (18.5%) from South or Central America, and n = 847 (6.7%) from the Dominican Republic. After controlling for age, sex, histology, grade, insurance status and treating facility type, we found that geographic origin was a significant predictor of advanced stage at diagnosis (P = .015). Compared to Cubans, patients of Puerto Rican origin were less likely to present with advanced disease (68.4% vs. 71.9%; OR: 0.82; 95%CI: 0.69-0.98; P = .026). We also identified a significant (log-rank P-value<.001) difference in OS by geographic origin, even at early-stages of diagnosis. Dominican patients with NSCLC exhibited the highest 5-year OS rate (63.3%), followed by patients from South/Central America (59.7%), Puerto Rico (52.3%), Mexico (45.9%), and Cuba (43.8%). CONCLUSION: This study showed that for Hispanic individuals living in the Unites states, region/country of origin is significantly associated with outcomes, even after accounting for other known determinants of health. We suggest that region of origin should be studied further as a potential determinant of outcomes in patients with cancer.

Factors Associated with the Decision to Decline Chemotherapy in Metastatic Non-Small Cell Lung Cancer.

(1) Background: Disparities in cancer treatment and outcomes have long been well-documented in the medical literature. With the eruption of advances in new treatment modalities, the long-existing disparities are now being further uncovered and brought to the attention of the medical community. While social health determinants have previously been linked to treatment disparities in lung cancer, we analyzed data from the National Cancer Database to explore sociodemographic and geographic factors related to accepting or declining physician-recommended chemotherapy. Patients diagnosed with metastatic lung cancer between 2004 and 2016 who declined chemotherapy recommended by their physicians were included in this study. Multivariate logistic regression analysis was performed. Cox Regression and Kaplan-Meier analyses were performed to look for survival characteristics. (2) Results: 316,826 patients with Stage IV lung cancer were identified. Factors related to a higher rate of refusal by patients included older age > 70, female sex, low income, lack of insurance coverage, residency in the New England region, and higher comorbidity. Patients living in areas with lower education were less likely to decline chemotherapy. (3) Conclusion: Further understanding of the factors impacting treatment decisions would be essential to improve the efficacy of care delivery in patients with cancer and reduce reversible causes of disparity.

Social disparities in pain management provision in stage IV lung cancer: A national registry analysis.

A strong association exists between pain and lung cancer (LC). Focusing on the disparities in pain referral in LC patients, we are aiming to characterize the prevalence and patterns of referrals to pain management (PM) in Stage IV non-small-cell LC (NSLC) and small-cell LC (SCLC). We sampled the National Cancer Database for de novo stage IV LC (2004-2016). We analyzed trends of pain referral using the Cochran-Armitage test. Chi-squared statistics were used to identify the sociodemographic and clinico-pathologic determinants of referral to PM, and significant variables (P < .05) were included in one multivariable regression model predicting the likelihood of pain referral. A total N = 17,620 (3.1%) of NSLC and N = 4305 (2.9%) SCLC patients were referred to PM. A significant increase in referrals was observed between 2004 and 2016 (NSLC: 1.7%-4.1%, P < .001; SCLC: 1.6%-4.2%, P < .001). Patient and disease factors played a significant role in likelihood of referral in both groups. Demographic factors such as gender, age, and facility type played a role in the likelihood of pain referrals, highlighting the gap and need for multidisciplinary PM in patients with LC. Despite an increase in the proportion of referrals to PM issued for terminal stage LC, the overall proportion remains low. To ensure better of quality of life for patients, oncologists need to be made aware of existent disparities and implicit biases.

Efficacy of chemotherapy in patients with HR+/HER2-Invasive lobular breast cancer.

INTRODUCTION: Invasive Lobular Breast Cancer (ILC) harbors unique clinicopathologic features. Data on optimal treatment modalities focusing on ILC remain scarce. We aim to investigate the benefit of chemotherapy in early-stage hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) ILC. METHODS: Female patients with early HR+/HER2- ILC (stages I-III) who underwent surgery were selected from the National Cancer Database (2010-2016) and grouped into four treatment cohorts: surgery only(S), chemotherapy alone (CT), endocrine therapy alone (ET), and combined chemotherapy followed by endocrine therapy (CET). Descriptive and bi-variate statistics summarized baseline characteristics and compared them across cohorts. A secondary analysis accounting for OncotypeDX (ODX) information was performed, stratifying for low (<26) and high (≥26) ODX. Kaplan-Meier (KM) and Cox proportional hazard models evaluated the relationship between treatment modality and overall survival (OS), stratifying for ODX scoring. RESULTS: N = 15,271 patients were included. The CET cohort (29.8%) was more likely to be younger and have no co-morbidities, advanced tumor stage or high ODX score (≥26). No significant difference in OS comparing ET to CET (HR:1.08, 95%CI:0.93-1.26, p = 0.31) was observed, adjusting for confounders. N = 5,561 patients had ODX results available. No significant difference in 5-year OS was observed comparing the ET to CET cohorts, both in patients an ODX score <26 (HR:1.10; 95%CI:0.69-1.76, p = 0.69) and ODX score ≥26 (HR:1.18; 95%CI:0.51-2.75, p = 0.69). CONCLUSION: Chemotherapy demonstrated no added survival benefit in HR+/HER2- ILC, even in tumors with ODX ≥26. Prospective trials identifying potential subgroups of patients with ILC who could benefit from chemotherapy are needed.

Does the 21-gene recurrence score have clinical utility in HR+/HER2+ breast cancer?

The 21-gene recurrence score assay has been validated as a predictive biomarker in early-stage HR+ and HER2-breast cancer. It is not indicated for use in HER2+ disease based on national guidelines. In this study, we assessed the value of 21-gene recurrence score (RS), or OncotypeDX (ODX), testing in HR+/HER2+ breast cancer. We used the National Cancer Database to identify patients with stages I-II, HR+/HER2+ breast cancer who received multi-gene testing with ODX. We then explored the prognostic and predictive value of this biomarker through various forms of survival modeling. ODX testing was performed in n = 5,280 patients. N = 2,678 patients (50.7%) had a RS < 26, while n = 2,602 (49.3%) had a RS ≥26. In Kaplan-Meier survival modeling for patients with recurrence scores <26, there was no significant difference in overall survival (p = 0.445) between patients receiving different systemic treatment regimens. However, when recurrence scores were ≥26, there was a statistically-significant difference in overall survival between systemic treatment regimens (p < 0.001). 5-year overall survival was highest (97.4%) for patients receiving triple therapy (anti-HER2 with chemotherapy and endocrine therapy), followed by those receiving dual therapy with endocrine and anti-HER2 (96.7%), and endocrine with chemotherapy (94.9%). Patients receiving endocrine therapy alone exhibited the lowest 5-year overall survival (88.5%). RESULTS: Analysis from this large national cancer registry suggests that multigene testing may have predictive value in treatment selection for patients with early-stage, HR+/HER2+ breast cancer. Prospective trials are warranted to identify subgroups of patients with HR+/HER2+ breast cancer who can be spared anti-HER2 treatments and cytotoxic chemotherapy.

Management of HR+/HER2+ lobular breast cancer and trends do not mirror better outcomes.

PURPOSE: Treatment protocols for invasive lobular breast cancer (ILC) have largely followed those for invasive ductal breast cancer. This study compares treatment outcomes of endocrine therapy versus combined chemo-endocrine therapy in hormone-receptor-positive (HR+), HER2-positive (HER2+) ILC tumors in a large national registry. METHODS: We sampled the National Cancer Database (2010-2016) for female patients with stages I-III, HR+/HER2+ ILC who underwent surgery. Cochran-Armitage trend test examined trends of treatment regimen administration: Surgery only (S), chemotherapy (C), endocrine therapy (ET), and combined chemo-endocrine therapy (CET), with or without anti-HER2 therapy. Cox proportional hazard model were used to compare overall survival (OS) across ET and CET cohorts, stratifying for anti-HER2 therapy, before and after propensity score match of cohorts (2013-2016). Kaplan-Meier (KM) survival curves were also produced. RESULTS: N=11,421 were included. 58.7% of patients received Anti-Her2 therapy after 2013. CET conferred better OS over ET in the unmatched (adjusted-5-year-OS: 92.5% vs. 81.1%, p<0.001) and PS-matched (90.4% vs. 84.5%, p=0.001) samples. ET caused lower OS in patients who received Anti-Her2 therapy (HR: 2.56, 95% CI: 1.60-4.12, p<0.001) and patients who did not (HR: 1.84, 95% CI: 1.21-2.78, p=0.004), as compared to CET on multivariable analysis. KM modeling showed highest OS in the CET cohort who received Anti-Her2 (93.0%), followed by the CET cohort who did not receive Anti-Her2 (90.2%) (p=0.06). CONCLUSION: Chemotherapy followed by endocrine therapy and Anti-Her2 therapy was shown to be the most effective treatment modality in HR+/HER2+ ILC, contrasting previous data on the inconclusive benefit of chemotherapy in patients with ILC.

Metastasectomy versus radiation of secondary sites in stage IV breast cancer: Analysis from a national cancer registry.

PURPOSE: Locoregional therapy at primary or secondary sites in breast cancer may be associated with improved survival as compared to systemic therapy alone. We explored the sociodemographic and clinicopathologic factors associated with the use of radiation versus surgical resection of metastatic sites (metastasectomy) in patients with de novo stage IV breast cancer, followed by the associated overall survival. METHODS: We sampled the National Cancer Database for patients with de novo stage IV breast cancer, (2010-2017) and described cohort's characteristics using univariate analyses. We identified 5 subgroups based on malignant site involvement: 1. Bone only, 2. Brain only, 3. Liver only, 4. Lung only, and 5. Metastasis involving >1 site. Kaplan-Meier modeling with log-rank testing and multivariate Cox Regression analysis were used to explore differences in overall survival between those that received radiation at secondary sites and those that underwent metastasectomy. RESULTS: N = 22,749patients were included in this analysis. Radiation (81.2%) was used more commonly than metastasectomy (28.8%). Metastasectomy was associated with better median overall survival across all 5 cohorts (p < .001), with the survival benefit being the most pronounced with lung only (OS: 56.9 months; HR 0.8, 95% CI 0.7-0.9, p = .032), or liver only (OS: 41.6 months; HR: 0.9; 95% CI: 0.7-1.1, p < .001) metastasis. CONCLUSION: Metastasectomy in patients with de novo stage IV breast cancer may be associated with improved overall survival as compared to radiation of secondary lesions, particularly in those with only liver or lung involvement. Prospective randomized controlled trials investigating surgical resection of metastatic sites in patients with breast cancer are warranted.

Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics.

BACKGROUND: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. PATIENTS AND METHODS: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16lowcells (immature) by flow cytometry. RESULTS: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%. CONCLUSION: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance.

Association of the prognostic model iSEND with PD-1/L1 monotherapy outcome in non-small-cell lung cancer.

BACKGROUND: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR). METHODS: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events. RESULTS: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort. CONCLUSION: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.

Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer.

INTRODUCTION: Presently, programmed death ligand 1 is the most commonly used biomarker to predict response to immune checkpoint inhibitors (ICIs) in NSCLC. Owing to its several limitations, there is continuous search for more precise and reliable markers. Frameshift mutations by insertion or deletion (fsindels) are suggested to induce more immunogenic tumor-specific neoantigens, conferring better response to ICIs. Positive correlation of fsindels with ICI response has been studied in melanoma and renal cell carcinoma. We investigated the implication of fsindels in the clinical outcomes and immune landscape of patients with NSCLC treated with ICIs. METHODS: We utilized The Cancer Genome Atlas data set to analyze tumor mutational burden, neoantigen burden, and immune landscape in relation to fsindel status. In addition, utilizing the clinical data from 122 patients treated with ICIs, we evaluated the influence of fsindels on disease response rates and survival outcomes. RESULTS: A positive correlation between fsindel burden and tumor mutational burden and activated CD4/CD8 T-cell infiltration was shown. Presence of fsindels was also associated with significant prolongation of progression-free survival in patients treated with ICIs (median 6.2 versus 2.7 months [p = 0.01]). In addition, significant differences in the overall response rates (26% versus 12% [p = 0.04]) and disease control rates (68% versus 48% [p = 0.02]) were observed in patients with fsindels. CONCLUSION: Our findings suggest that fsindels may have a predictive role for ICI response in NSCLC.

Developing a Predictive Model for Clinical Outcomes of Advanced Non-Small Cell Lung Cancer Patients Treated With Nivolumab.

INTRODUCTION: Despite significant improvement of clinical outcomes of advanced non-small-cell lung cancer (NSCLC) patients treated with immunotherapy, our knowledge of optimal biomarkers is still limited. PATIENTS AND METHODS: We retrospectively evaluated 159 advanced NSCLC patients in our institution treated with nivolumab after disease progression during platinum-based chemotherapy. We correlated several variables with progression-free survival (PFS) to develop the immunotherapy, Sex, Eastern Cooperative Oncology Group performance status, Neutrophil-to-lymphocyte ratio (NLR), and Delta NLR (iSEND) model. We categorized patients into iSEND good, intermediate, and poor risk groups and evaluated their clinical outcomes. Performance of iSEND at 3, 6, 9, and 12 months was evaluated according to receiver operating characteristic (ROC) curves and internally validated using bootstrapping. The association of iSEND risk groups with clinical benefit was evaluated using logistic regression. RESULTS: Median follow-up was 11.5 months (95% confidence interval [CI], 9.4-13.1). There were 50 deaths and 43 with disease progression without death. PFS rates at 3, 6, 9, and 12 months were 78.4%, 63.7%, 55.3%, and 52.2% in iSEND good; 79.4%, 44.3%, 25.9%, and 19.2% in iSEND intermediate; and 65%, 25.9%, 22.8%, and 17.8% in iSEND poor. Time-dependent area under ROC curves of iSEND for PFS at 3, 6, 9, and 12 months were 0.718, 0.74, 0.746, and 0.774. The iSEND poor group was significantly associated with progressive disease at 12 ± 2 weeks (odds ratio, 9.59; 95% CI, 3.8-26.9; P < .0001). CONCLUSION: The iSEND model is an algorithmic model that can characterize clinical outcomes of advanced NSCLC patients receiving nivolumab into good, intermediate, or poor risk groups and might be useful as a predictive model if validated independently.

Time from nephrectomy as a prognostic factor in metastatic renal cell carcinoma patients receiving targeted therapies: overall results from a large cohort of patients.

OBJECTIVE: To investigate whether time from nephrectomy (Nx) to the diagnosis of metastatic disease may be an independent prognostic factor in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies (TTs). SUBJECTS AND METHODS: All patients who underwent Nx and at least 1 TT were considered. The patients were divided into two groups based on time from Nx [>1 year (Nx >1) and <1 year (Nx <1)] and a third group for cytoreductive Nx (cNx). Median overall survival (OS) represented the primary outcome. RESULTS: A total of 297 patients met the inclusion criteria. The time from Nx was >1 year in 47%, <1 year in 26% and concomitant with the diagnosis of metastatic disease in 27% of the cases (i.e. cNx). The median OS was 40.6 months (95% CI 30.5-50.7) for the Nx >1 group, 24.3 months (95% CI 17.7-31) for the Nx <1 group and 16.2 months (95% CI 11.2-21.3) for the cNx group (p < 0.05 for all comparisons). On multivariate analysis, time from Nx resulted to be an independent prognostic factor (Nx <1 vs. cNx: HR = 0.62, 95% CI 0.42-0.90, p = 0.13; Nx >1 vs. cNx: HR = 0.43, 95% CI 0.31-0.61, p < 0.001). CONCLUSION: We report that time from Nx is an independent prognostic factor for OS in patients affected by mRCC treated with TTs.