Comparative effectiveness of treatment approaches for early invasive breast cancer.

BACKGROUND: Randomized controlled trials (RCTs) suggested breast conserving therapy (BCT) and mastectomy have similar survival for early-stage breast cancer, whereas observational studies reported survival advantage for BCT. We aimed to address biases in observational studies to compare the effect of BCT and mastectomy on survival. METHODS: We emulated a target trial using institutional cancer registry. We included adult women diagnosed with early invasive first primary breast tumors ≤ 5 cm between July 2011 and December 2017. We used cloning, censoring, and weighting to estimate risk differences (RDs) and risk ratios (RRs) for all-cause mortality and recurrence or all-cause mortality between BCT and mastectomy (reference). RESULTS: Our study population comprised 534 observations with breast cancer. Median age was 56 years and 65 % were racial/ethnic minorities. The 8-year RD was 1.5 % (95 % confidence limits [CL]: -7.0 %, 9.8 %) and RR was 1.1 (95 % CL: 0.57, 2.2) for all-cause mortality. Results for recurrence or mortality were similar. CONCLUSIONS: Our results suggest that target trial emulation to mitigate selection and immortal-time biases in observational studies may generate estimates that are more compatible with RCTs when comparing the effects of BCT and mastectomy on survival. Studies with longer follow-up and more events are needed to confirm our findings.

Survival After Implementation of a Decision Support Tool to Facilitate Evidence-Based Cancer Treatment.

PURPOSE: Decision support tools (DSTs) to facilitate evidence-based cancer treatment are increasingly common in care delivery organizations. Implementation of these tools may improve process outcomes, but little is known about effects on patient outcomes such as survival. We aimed to evaluate the effect of implementing a DST for cancer treatment on overall survival (OS) among patients with breast, colorectal, and lung cancer. METHODS: We used institutional cancer registry data to identify adults treated for first primary breast, colorectal, or lung cancer between December 2013 and December 2017. Our intervention of interest was implementation of a commercial DST for cancer treatment, and outcome of interest was OS. We emulated a single-arm trial with historical comparison and used a flexible parametric model to estimate standardized 3-year restricted mean survival time (RMST) difference and mortality risk ratio (RR) with 95% confidence limits (CLs). RESULTS: Our study population comprised 1,059 patients with cancer (323 breast, 318 colorectal, and 418 lung). Depending on cancer type, median age was 55-60 years, 45%-67% were racial/ethnic minorities, and 49%-69% were uninsured. DST implementation had little effect on survival at 3 years. The largest effect was observed among patients with lung cancer (RMST difference, 1.7 months; 95% CL, -0.26 to 3.7; mortality RR, 0.95; 95% CL, 0.88 to 1.0). Adherence with tool-based treatment recommendations was >70% before and >90% across cancers. CONCLUSION: Our results suggest that implementation of a DST for cancer treatment has nominal effect on OS, which may be partially attributable to high adherence with evidence-based treatment recommendations before tool implementation in our setting. Our results raise awareness that improved process outcomes may not translate to improved patient outcomes in some care delivery settings.

Cardiotoxicity among socioeconomically marginalized breast cancer patients.

PURPOSE: Evidence of cardiotoxicity risk related to anthracycline or trastuzumab exposure is largely derived from breast cancer cohorts that under-represent socioeconomically marginalized women, who may be at increased risk of cardiotoxicity because of high prevalence of cardiovascular disease risk factors. Therefore, we aimed to estimate cardiotoxicity risk among socioeconomically marginalized breast cancer patients treated with anthracyclines or trastuzumab and describe clinical consequences of cardiotoxicity. METHODS: We linked electronic health records with institutional registry data from a Comprehensive Community Cancer Program within a safety-net health system. Eligible patients were adult females, diagnosed with first primary invasive breast cancer between 2013 and 2017, and initiated anthracyclines or trastuzumab as part of first-line therapy. We estimated cumulative incidence (risk) of cardiotoxicity with corresponding 95% confidence limits (CL) using the Aalen-Johansen estimator with death as competing risk. RESULTS: Our study population comprised 169 women with breast cancer (103 initiated anthracyclines and 66 initiated trastuzumab). Cumulative incidence of cardiotoxicity was 21% (95% CL: 12%, 32%) at one year and 25% (95% CL: 15%, 35%) at three years among women who initiated trastuzumab, whereas cumulative incidence was 3.9% (95% CL: 1.3%, 8.9%) at one year and 5.9% (95% CL: 2.4%, 12%) at three years among women who initiated anthracyclines. More than half of patients with cardiotoxicity experienced interruption of cancer treatment. CONCLUSION: Our findings suggest high risk of cardiotoxicity among socioeconomically marginalized breast cancer patients after initiation of anthracyclines or trastuzumab. Strategies are needed for optimizing cancer treatment effectiveness while minimizing cardiotoxicity in this population.

Timing of adjuvant chemotherapy initiation and mortality among colon cancer patients at a safety-net health system.

BACKGROUND: Prior studies reported survival benefits from early initiation of adjuvant chemotherapy for stage III colon cancer, but this evidence was derived from studies that may be sensitive to time-related biases. Therefore, we aimed to estimate the effect of initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks on overall and disease-free survival among stage III colon cancer patients using a study design that helps address time-related biases. METHODS: We used institutional registry data from JPS Oncology and Infusion Center, a Comprehensive Community Cancer Program. Eligible patients were adults aged < 80 years, diagnosed with first primary stage III colon cancer between 2011 and 2017, and received surgical resection with curative intent. We emulated a target trial with sequential eligibility. We subsequently pooled the trials and estimated risk ratios (RRs) along with 95% confidence limits (CL) for all-cause mortality and recurrence or death at 5-years between initiators and non-initiators of adjuvant chemotherapy ≤8 or ≤ 12 weeks using pseudo-observations and a marginal structural model with stabilized inverse probability of treatment weights. RESULTS: Our study population comprised 222 (for assessing initiation ≤8 weeks) and 310 (for assessing initiation ≤12 weeks) observations, of whom the majority were racial/ethnic minorities (64-65%), or uninsured with or without enrollment in our hospital-based medical assistance program (68-71%). Initiation of adjuvant chemotherapy ≤8 weeks of surgical resection did not improve overall survival (RR for all-cause mortality = 1.04, 95% CL: 0.57, 1.92) or disease-free survival (RR for recurrence or death = 1.07, 95% CL: 0.61, 1.88). The results were similar for initiation of adjuvant chemotherapy ≤12 weeks of surgical resection. CONCLUSIONS: Our results suggest that the overall and disease-free survival benefits of initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks of surgical resection may be overestimated in prior studies, which may be attributable to time-related biases. Nevertheless, our estimates were imprecise and differences in population characteristics are an alternate explanation. Additional studies that address time-related biases are needed to clarify our findings.

Impact of prognostic factor distributions on mortality disparities for socioeconomically disadvantaged cancer patients.

PURPOSE: We aimed to assess whether differences in the distributions of prognostic factors explain reported mortality disparities between urban safety-net and Surveillance, Epidemiology, and End Results (SEER) cancer populations. METHODS: We used data from SEER and a safety-net cancer center in Texas. Eligible patients were adults aged ≤64 years and diagnosed with first primary female breast, colorectal, or lung cancer between 2008 and 2016. We estimated crude and adjusted risk differences (RD) in 3- and 5-year all-cause mortality (1- and 3-year for lung cancer), where adjustment was based on entropy balancing weights that standardized the distribution of sociodemographic and tumor characteristics between the two populations. RESULTS: Our study populations comprised 1914 safety-net patients and 389,709 SEER patients. For breast cancer, the crude 3- and 5-year mortality RDs between safety-net and SEER populations were 7.7% (95% confidence limits [CL]: 4.3%, 11%) and 11% (95% CL: 6.7%, 16%). Adjustment for measured prognostic factors reduced the mortality RDs (3-year adjusted RD = 0.049%, 95% CL: -2.6%, 2.6%; 5-year adjusted RD = 5.6%, 95% CL: -0.83%, 12%). We observed similar patterns for colorectal and lung cancer albeit less magnitude. CONCLUSIONS: Sociodemographic and tumor characteristics may largely explain early mortality disparities between safety-net and SEER populations but not late mortality disparities.

Real-world performance of blood-based proteomic profiling in first-line immunotherapy treatment in advanced stage non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibition (ICI) therapy has improved patient outcomes in advanced non-small cell lung cancer (NSCLC), but better biomarkers are needed. A clinically validated, blood-based proteomic test, or host immune classifier (HIC), was assessed for its ability to predict ICI therapy outcomes in this real-world, prospectively designed, observational study. MATERIALS AND METHODS: The prospectively designed, observational registry study INSIGHT (Clinical Effectiveness Assessment of VeriStrat® Testing and Validation of Immunotherapy Tests in NSCLC Subjects) (NCT03289780) includes 35 US sites having enrolled over 3570 NSCLC patients at any stage and line of therapy. After enrolment and prior to therapy initiation, all patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C). A prespecified interim analysis was performed after 1-year follow-up with the first 2000 enrolled patients. We report the overall survival (OS) of patients with advanced stage (IIIB and IV) NSCLC treated in the first-line (ICI-containing therapies n=284; all first-line therapies n=877), by treatment type and in HIC-defined subgroups. RESULTS: OS for HIC-H patients was longer than OS for HIC-C patients across treatment regimens, including ICI. For patients treated with all ICI regimens, median OS was not reached (95% CI 15.4 to undefined months) for HIC-H (n=196) vs 5.0 months (95% CI 2.9 to 6.4) for HIC-C patients (n=88); HR=0.38 (95% CI 0.27 to 0.53), p<0.0001. For ICI monotherapy, OS was 16.8 vs 2.8 months (HR=0.36 (95% CI 0.22 to 0.58), p<0.0001) and for ICI with chemotherapy OS was unreached vs 6.4 months (HR=0.41 (95% CI 0.26 to 0.67), p=0.0003). HIC results were independent of programmed death ligand 1 (PD-L1). In a subgroup with PD-L1 ≥50% and performance status 0-1, HIC stratified survival significantly for ICI monotherapy but not ICI with chemotherapy. CONCLUSION: Blood-based HIC proteomic testing provides clinically meaningful information for immunotherapy treatment decision in NSCLC independent of PD-L1. The data suggest that HIC-C patients should not be treated with ICI alone regardless of their PD-L1 expression.

Current Perspectives in Immunotherapy for Liver Cancer.

Liver cancer is a particularly aggressive group of malignancies with historically low survival rates. Despite advancements in cancer treatments in general in the last few decades, incidence and mortality have not changed. Even though some phase 1 and 2 studies have shown promising results, many medication have failed to reach a sustainable level of efficacy to move into the clinical setting. Immunotherapy drugs have shown impressive results in the treatment of specific immunogenic cancers, prompting the possibility of their use in liver cancers. Immunotherapy medications approved for other cancers have received FDA accelerated approval for treatment of hepatocellular carcinoma. But, these approvals are contingent upon verification and description of clinical benefit in confirmatory trials. With more treatments in development involving cancer vaccines and natural killer cell-mediated therapy, liver cancer treatment is being reinvigorated with a broad array of new treatment angles. In this review article, we discuss these treatments, focusing on mechanism of action and clinical trials. Much needed advancements in treating late- and early-stage liver cancers will require new and innovative immunotherapeutic treatments.

Targeted Molecular Therapeutic Options for Hepatocellular Carcinoma.

Liver cancer is the 6th leading cause of cancer related deaths in the US even though it ranks 14th in incidence. More men are diagnosed with liver cancer than women, and the number of projected deaths among men (20,020) is almost double that among women (10,140) in the US. Infections like hepatitis and metabolic conditions like obesity are believed to be major risk factors for the onset of liver cancer. Hepatocellular carcinoma (HCC), the most common type of liver cancer, accounts for 75% of all cases. Chemotherapy has not been effective in treating HCC. Targeted therapies are being used in advanced HCC patients due to a better survival and less side effects when compared to traditional chemotherapy. Therapeutic agents targeting the regulators of growth factor signaling pathways and the mediators of downstream signaling-for example, inhibitors of the tyrosine kinase receptor-are used as targeted molecular therapies. Kinase inhibitors that modulate growth signals, such as sorafenib and lenvatinib, are commonly employed in targeted molecular therapy for HCC patients. This review covers these agents, highlighting modes of action and providing details on clinical trials.

Smoking cessation and survival among people diagnosed with non-metastatic cancer.

BACKGROUND: We aimed to estimate the effects of smoking cessation on survival among people diagnosed with cancer. METHODS: We used data from a Comprehensive Community Cancer Program that is part of a large urban safety-net hospital system. Eligible patients were diagnosed with primary invasive solid tumors between 2013 and 2015, and were current smokers at time of diagnosis. Our exposure of interest was initiation of smoking cessation within 6 months of cancer diagnosis. We estimated inverse probability weighted restricted mean survival time (RMST) differences and risk ratio (RR) for all cause 3-year mortality. RESULTS: Our study population comprised 369 patients, of whom 42% were aged < 55 years, 59% were male, 44% were racial/ethnic minorities, and 59% were uninsured. The 3-year RMST was 1.8 (95% CL: - 1.5, 5.1) months longer for individuals who initiated smoking cessation within 6 months of cancer diagnosis. The point estimate for risk of 3-year mortality was lower for initiation of smoking cessation within 6 months of diagnosis compared with no initiation within 6 months (RR = 0.72, 95% CL: 0.37, 1.4). CONCLUSIONS: Our point estimates suggest longer 3-year survival, but the results are compatible with 1.5 month shorter or 5.1 longer 3-year overall survival after smoking cessation within 6 months of cancer diagnosis. Future studies with larger sample sizes that test the comparative effectiveness of different smoking cessation strategies are needed for more detailed evidence to inform decision-making about the effect of smoking cessation on survival among cancer patients. IMPLICATIONS FOR CANCER SURVIVORS: The benefits of smoking cessation after cancer diagnosis may include longer survival, but the magnitude of benefit is unclear.

Adult Cancer Survivors' Engagement and Interest in Patient-Centered Research.

BACKGROUND: Limited information is available about the representativeness of survivors engaging in patient-centered research, despite the potential for threats to generalizability. We thus aimed to assess the representativeness of survivors engaged or interested in research development. METHODS: We used data from the Health Information National Trends Survey, a nationally representative survey, to identify survivors of adult cancers. Our outcomes of interest were based on responses to questions about engagement or interest in developing patient-centered research. We estimated the ratio of relative frequencies (RRF) and corresponding 95% confidence limits (CL) of sociodemographic and survivorship characteristics between survivors engaged or interested in patient-centered research and the overall survivor population. RESULTS: Our study population comprised 934 survivors, of whom 5% reported being engaged in patient-centered research and 26% reported an interest in participating. Relative frequencies of characteristics were discordant for engaged survivors but largely similar for interested survivors compared with all survivors. In particular, engaged survivors had a higher relative frequency of individuals ages 50 to 64 years (RRF = 1.7; 95% CL, 1.1-2.5), Hispanic (RRF = 2.9; 95% CL, 1.2-6.9), non-Hispanic Black (RRF = 2.9; 95% CL, 1.1-2.5), and unemployment (RRF = 4.7; 95% CL, 1.4-16). CONCLUSIONS: We observed several meaningful differences in the characteristics of survivors engaged in patient-centered research compared with all survivors, which raises concerns about the generalizability of findings from such studies. IMPACT: Patient-centered research may not benefit the broader survivor community if survivors engaging in research development are not representative of all survivors. Greater attention to recruiting mechanisms is necessary to avoid creating disparities.

Affordable Care Act and cancer stage at diagnosis in an underserved population.

The Patient Protection and Affordable Care Act (ACA) has increased insurance coverage among underserved individuals, but the effect of ACA on cancer diagnosis is currently debated, particularly in Medicaid non-expansion states. Therefore, we aimed to assess the effect of ACA implementation on stage at diagnosis among underserved cancer patients in Texas, a Medicaid non-expansion state. We used data from the institutional registry of the JPS Center for Cancer Care, which serves an urban population of underserved cancer patients. Eligible individuals were aged 18 to 64 years and diagnosed with a first primary invasive solid tumor between 2008 and 2015. We used a natural experiment framework and interrupted time-series analysis to assess level (i.e. immediate) and slope (over time) changes in insurance coverage and cancer stage at diagnosis between pre- and post-ACA periods. Our study population comprised 4808 underserved cancer patients, of whom 51% were racial/ethnic minorities. The prevalence of uninsured cancer patients did not immediately change after ACA implementation but modestly decreased over time (PR = 0.94; 95% CL: 0.90, 0.98). The prevalence of early- and advanced-stage diagnosis did not appreciably change overall or when stratified by screen-detectable cancers. Our results suggest that ACA implementation decreased the prevalence of uninsured cancer patients but had little effect on cancer stage at diagnosis in an underserved population. Given that Texas is a Medicaid non-expansion state, Medicaid expansion and alternative approaches may need to be further explored to improve earlier cancer diagnosis among underserved individuals.

A population-based study of incidence and patient survival of small cell carcinoma in the United States, 1992-2010.

BACKGROUND: In contrast to the well-described epidemiology and behavior of small cell lung carcinoma (SCLC), little is known about extrapulmonary small cell carcinoma (EPSCC). METHODS: Using data from the Surveillance, Epidemiology and End Results (SEER) Program (1992-2010), we calculated age-adjusted incidence rates (IRs), IR ratios (IRRs), annual percent change (APC), relative survival (RS), RS ratios (RSRs), and the respective 95% confidence intervals (95% CI) of SCLC and EPSCC according to primary site. We used the SEER historic stage variable that includes localized (confined to the organ of origin), regional (direct extension to adjacent organ/tissue or regional lymph nodes), and distant (discontinuous metastases) stages and combined localized and regional stages into "limited" stage. RESULTS: The incidence of SCLC (IR = 76.3/million person-years; n = 51,959) was 22-times that of EPSCC (IR = 3.5; n = 2,438). Of the EPSCC sites, urinary bladder, prostate, and uterine cervix had the highest incidence (IRs = 0.7-0.8); urinary bladder (IRR = 4.91) and stomach (IRR = 3.46) had the greatest male/female disparities. Distant-to-limited stage site-specific IRRs of EPSCC were significantly elevated for pancreas (IRR = 6.87; P < 0.05), stomach, colon/rectum, ovary, and prostate (IRRs = 1.62-2.42; P < 0.05) and significantly decreased for salivary glands, female breast, uterine cervix, and urinary bladder (IRRs = 0.32-0.46). During 1992-2010, significant changes in IRs were observed for EPSCC overall (APC = 1.58), small cell carcinoma of the urinary bladder (APC = 6.75), SCLC (APC = -2.74) and small cell carcinoma of unknown primary site (APC = -4.34). Three-year RS was significantly more favorable for patients with EPSCC than SCLC for both limited (RSR = 2.06; 95% CI 1.88, 2.26) and distant stages (RSR = 1.55; 95% CI 1.16, 2.07). Among limited stage small cell carcinoma, RS was most favorable for salivary glands, female breast, and uterine cervix (RS = 52-68%), whereas RS for nearly all sites with distant stage disease was <10%. CONCLUSION: EPSCC comprises a heterogeneous group of diseases that appears, at least in part, etiologically distinct from SCLC and is associated with more favorable stage-specific patient survival.

Head and neck carcinoma in the United States: first comprehensive report of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN).

BACKGROUND: Detailed information about how patients with head and neck carcinoma (HNC) are treated across practice settings does not exist. The authors conducted a prospective, observational study to examine the patterns of care for a series of patients with newly diagnosed HNC in the United States and to test 2 hypotheses: 1) There is no difference in the pattern of care between community and academic settings; and 2) the results of major randomized clinical trials will change the pattern of care in both practice settings within 1 year of publication in peer-reviewed journals. METHODS: Patients aged ≥ 18 years were enrolled in the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN) after providing written informed consent if they had a confirmed diagnosis of new HNC and were scheduled to receive treatment other than surgery alone. RESULTS: Between 2005 and 2010, 100 centers enrolled 4243 patients, including 2612 patients (62%) from academic investigators and 1631 patients (38%) from community centers. Initial treatments were radiation with concurrent chemotherapy (30%) or cetuximab (9%), adjuvant radiotherapy (21%), induction chemotherapy (16%), and other (24%). Intensity modulated radiation therapy was the dominant radiation technique (84%). Single-agent cisplatin was prescribed in nearly half of patients and more often in academic centers (53% vs 43% of patients; P < .0001). Single-agent cetuximab was the next most common drug used (19%) and was prescribed more frequently in community settings (24% vs 17%; P = .0001). The data rejected the 2 prospective hypotheses. CONCLUSIONS: LORHAN documented differences in patient characteristics and treatments between community and academic settings for a large series of patients in the United States.

Adenoid cystic carcinoma of the breast in the United States (1977 to 2006): a population-based cohort study.

INTRODUCTION: Adenoid cystic carcinoma of the breast (breast-ACC) is a rare and special type of basal-like tumor for which scant population-based descriptive data exist. We sought to provide new population-based information on breast-ACC incidence, relative survival, and associated cancer risk in the United States. METHODS: Using data from the Surveillance, Epidemiology and End Results Program, we calculated age-adjusted incidence rates (IRs), IR ratios (IRRs), and relative survival for breast-ACC, and standardized incidence ratios (SIRs) for other cancers. RESULTS: Overall 338 women (IR = 0.92/1 million person-years) were diagnosed with breast-ACC during 1977 to 2006. Blacks had 39% lower IRs than Whites (IRR = 0.61, 95% confidence interval = 0.37 to 0.96), and IRs remained constant over the 30-year period. Ninety-five percent of cases presented with localized stage (n = 320; IR = 0.87), and the highest IRs were observed for estrogen receptor (ER)-negative/progesterone receptor (PR)-negative tumors (IR = 0.56). Like other typically ER-negative tumors, age-specific IRs increased until midlife and then plateaued. Five-year, 10-year, and 15-year relative survival was 98.1%, 94.9%, and 91.4%, respectively. The risk of female breast cancer was not increased following (SIR = 0.89, 95% confidence interval = 0.43 to 1.64) or preceding (SIR = 0.71, 95% confidence interval = 0.28 to 1.46) breast-ACC. Similarly, no association was observed for breast-ACC and risk of all other cancers combined, solid tumors, or lymphohematopoietic malignancies. CONCLUSIONS: Breast-ACC among women is characterized by ER-negative/PR-negative expression, rare regional lymph node involvement, a favorable prognosis with excellent survival, and absence of associated cancers. These findings reinforce the importance of tailored treatments for breast-ACC and lend credence to the apparent heterogeneity of basal-like breast cancers.