Leveraging existing data to contextualize phase II clinical trial findings in oncology

More than 250 000 women are diagnosed with early-stage breast cancer (EBC) in the USA each year. Of these, up to 30% have amplification of the human epidermal growth factor 2 (HER2). The current standard of care for HER2-positive (HER2þ) EBC is chemotherapy plus HER2-directed therapy to complete 1 year of treatment. There is growing interest in determining which patients with HER2þ tumors could achieve favorable outcomes with less chemotherapy through better HER2-targeting. The phase II Adjuvant Paclitaxel and Trastuzumab (APT) trial by Tolaney and colleagues provided compelling evidence that patients with small HER2þ tumors without nodal macrometastases can achieve highly favorable outcomes with paclitaxel and trastuzumab alone (TH), avoiding the toxicity associated with multi-agent chemotherapy regimens. Use of TH in this context has been widely adopted in the clinical setting despite the lack of a confirmatory phase III trial

Formal change impact analyses for emulated control software

Processor emulators are a software tool for allowing legacy computer programs to be executed on a modern processor. In the past emulators have been used in trivial applications such as maintenance of video games. Now, however, processor emulation is being applied to safety-critical control systems, including military avionics. These applications demand utmost guarantees of correctness, but no verification techniques exist for proving that an emulated system preserves the original system’s functional and timing properties. Here we show how this can be done by combining concepts previously used for reasoning about real-time program compilation, coupled with an understanding of the new and old software architectures. In particular, we show how both the old and new systems can be given a common semantics, thus allowing their behaviours to be compared directly

Mode transitions in a model reaction-diffusion system driven by domain growth and noise

Pattern formation in many biological systems takes place during growth of the underlying domain. We study a specific example of a reaction–diffusion (Turing) model in which peak splitting, driven by domain growth, generates a sequence of patterns. We have previously shown that the pattern sequences which are presented when the domain growth rate is sufficiently rapid exhibit a mode-doubling phenomenon. Such pattern sequences afford reliable selection of certain final patterns, thus addressing the robustness problem inherent of the Turing mechanism. At slower domain growth rates this regular mode doubling breaks down in the presence of small perturbations to the dynamics. In this paper we examine the breaking down of the mode doubling sequence and consider the implications of this behaviour in increasing the range of reliably selectable final patterns

Financial impact of breast cancer in black versus white women

Purpose Racial variation in the financial impact of cancer may contribute to observed differences in the use of guideline-recommended treatments. We describe racial differences with regard to the financial impact of breast cancer in a large population-based prospective cohort study. Methods The Carolina Breast Cancer Study oversampled black women and women younger than age 50 years with incident breast cancer in North Carolina from 2008 to 2013. Participants provided medical records and data regarding demographics, socioeconomic status, and financial impact of cancer at 5 and 25 months postdiagnosis. We report unadjusted and adjusted financial impact at 25 months postdiagnosis by race. Results The sample included 2,494 women who completed follow-up surveys (49% black, 51% white). Since diagnosis, 58% of black women reported any adverse financial impact of cancer (v 39% of white women; P, .001). In models adjusted for age, stage at diagnosis, and treatment received, black women were more likely to report adverse financial impact attributable to cancer (adjusted risk difference [aRD], +14 percentage points; P, .001), including income loss (aRD, +10 percentage points; P, .001), health care–related financial barriers (aRD, +10 percentage points; P, .001), health care–related transportation barriers (aRD, +10 percentage points; P, .001), job loss (aRD, 6 percentage points; P, .001), and loss of health insurance (aRD, +3 percentage points; P, .001). The effect of race was attenuated when socioeconomic factors were included but remained significant for job loss, transportation barriers, income loss, and overall financial impact. Conclusion Compared with white women, black women with breast cancer experience a significantly worse financial impact. Disproportionate financial strain may contribute to higher stress, lower treatment compliance, and worse outcomes by race. Policies that help to limit the effect of cancer-related financial strain are needed

Comparative toxicity and effectiveness of trastuzumab-based chemotherapy regimens in older women with early-stage breast cancer

Purpose The combination of chemotherapy and trastuzumab is the standard of care for adjuvant treatment of human epidermal growth factor receptor 2-positive breast cancer. Two regimens have been widely adopted in the United States: doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab (ACTH) and docetaxel, carboplatin, and trastuzumab (TCH). No head-to-head comparison of these regimens has been conducted in a clinical trial, and existing trial data have limited generalizability to older patients. Methods We used SEER-Medicare data from 2005 to 2013 to compare outcomes of ACTH versus TCH among patients age older than 65 years. Propensity score matching was used to balance cohort characteristics between treatment arms. Outcomes included toxicity-related hospitalization, survival, and trastuzumab completion. Data from 1,077 patients receiving ACTH or TCH were analyzed, and the propensity-matched subsample included 416 women. Results There was a significant shift toward TCH over time, with 88% of patients receiving ACTH in 2005 compared with 15% by 2011. Among propensity score-matched patients, we found no difference between regimens in health care use overall or for chemotherapy-related adverse events (ACTH, 34% v TCH, 36.5%; P = .46). Patients receiving TCH were significantly more likely to complete trastuzumab (89% v 77%; P = .001). There was no difference in 5-year breast cancer-specific survival (ACTH, 92% v TCH, 96%; hazard ratio, 2.08; 95% CI, 0.90 to 4.82) or overall survival. Conclusion Among a matched sample of older patients, ACTH compared with TCH was not associated with a higher rate of serious adverse events or hospitalizations, but it was associated with less completion of adjuvant trastuzumab.Wedid not detect a difference in 5-year survival outcomes for ACTH compared with TCH. In the context of limited evidence in older patients, selection between these two regimens on the basis of concerns about differential toxicity or efficacy may not be appropriate

Burden of lymphedema in long-term breast cancer survivors by race and age

Background: Risk assessment for breast cancer–related lymphedema has emphasized upper-limb symptoms and treatment-related risk factors. This article examined breast cancer–related lymphedema after surgery, overall and in association with broader demographic and clinical features. Methods: The Carolina Breast Cancer Study phase 3 followed participants for breast cancer–related lymphedema from baseline (on average, 5 months after breast cancer diagnosis) to 7 years after diagnosis. Among 2645 participants, 552 self-reported lymphedema cases were identified. Time-to-lymphedema curves and inverse probability weighted conditional Cox proportional hazards model were used to evaluate whether demographics and clinical features were associated with breast cancer–related lymphedema. Results: Point prevalence of breast cancer–related lymphedema was 6.8% at baseline, and 19.9% and 23.8% at 2 and 7 years after diagnosis, respectively. Most cases had lymphedema in the arm (88%-93%), whereas 14% to 27% presented in the trunk and/or breast. Beginning approximately 10 months after diagnosis, younger Black women had the highest risk of breast cancer–related lymphedema and older non-Black women had the lowest risk. Positive lymph node status, larger tumor size (>5 cm), and estrogen receptor–negative breast cancer, as well as established risk factors such as higher body mass index, removal of more than five lymph nodes, mastectomy, chemotherapy, and radiation therapy, were significantly associated with increased hazard (1.5- to 3.5-fold) of lymphedema. Conclusions: Findings highlight that hazard of breast cancer–related lymphedema differs by demographic characteristics and clinical features. These factors could be used to identify those at greatest need of lymphedema prevention and early intervention. Lay summary: In this study, the aim was to investigate breast cancer–related lymphedema (BCRL) burden. This study found that risk of BCRL differs by race, age, and other characteristics

Race and delays in breast cancer treatment across the care continuum in the Carolina Breast Cancer Study

Background: After controlling for baseline disease factors, researchers have found that black women have worse breast cancer survival, and this suggests that treatment differences may contribute to poorer outcomes. Delays in initiating and completing treatment are one proposed mechanism. Methods: Phase 3 of the Carolina Breast Cancer Study involved a large, population-based cohort of women with incident breast cancer. For this analysis, we included black women (n = 1328) and white women (n = 1331) with stage I to III disease whose treatment included surgery with or without adjuvant therapies. A novel treatment pathway grouping was used to benchmark the treatment duration (surgery only, surgery plus chemotherapy, surgery plus radiation, or all 3). Models controlled for the treatment pathway, age, and tumor characteristics and for demographic factors related to health care access. Exploratory analyses of the association between delays and cancer recurrence were performed. Results: In fully adjusted analyses, blacks had 1.73 times higher odds of treatment initiation more than 60 days after their diagnosis in comparison with whites (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.04-2.90). Black race was also associated with a longer treatment duration. Blacks were also more likely to be in the highest quartile of treatment duration (OR, 1.69; 95% CI, 1.41-2.02), even after adjustments for demographic and tumor characteristics (OR, 1.31; 95% CI, 1.04-1.64). A nonsignificant trend toward a higher recurrence risk was observed for patients with delayed initiation (hazard ratio, 1.44; 95% CI, 0.89-2.33) or the longest duration (hazard ratio, 1.17; 95% CI, 0.87-1.59). Conclusions: Black women more often had delayed treatment initiation and a longer duration than whites receiving similar treatment. Interventions that target access barriers may be needed to improve timely delivery of care

Influence of provider factors and race on uptake of breast cancer gene expression profiling

BACKGROUND: Gene expression profiling (GEP) has been rapidly adopted for early breast cancer and can aid in chemotherapy decision making. Study results regarding racial disparities in testing are conflicting, and may reflect different care settings. To the authors' knowledge, data regarding the influence of provider factors on testing are scarce. METHODS: The authors used a statewide, multipayer, insurance claims database linked to cancer registry records to examine the impact of race and provider characteristics on GEP uptake in a cohort of patients newly diagnosed with breast cancer between 2005 and 2012. Incidence proportion models were used to examine the adjusted likelihood of testing. Models were stratified by lymph node status (N0 vs N1). RESULTS: Among 11,958 eligible patients, 23% of black and 26% of non-Hispanic white patients received GEP. Among patients with N0 disease, black individuals were 16% less likely to receive testing after adjustment for clinical factors and the provider's specialty and volume of patients with breast cancer (95% confidence interval, 0.77-0.93). Adjustment for provider characteristics did not attenuate the effect of race on testing. Patients of middle-volume providers were more likely to be tested compared with those with either high-volume or low-volume providers, whereas patients seeing a medical oncologist were more likely to be tested compared with those whose only providers were from surgical specialties. CONCLUSIONS: Provider volume and specialty were found to be significant predictors of GEP use, but did not explain racial disparities in testing. Further research concerning the key contributors to lagging test use among black women is needed to optimize the equitable use of GEPs and support personalized treatment decision making for all patients

Borderline estrogen receptor-positive breast cancers in black and white women

Background: Some breast tumors expressing greater than 1% and less than 10% estrogen receptor (ER) positivity (ER-borderline) are clinically aggressive; others exhibit luminal biology. Prior ER-borderline studies included few black participants. Methods: Using the Carolina Breast Cancer Study (phase I: 1993-1996; 2: 1996-2001; 3: 2008-2013), a population-based study that oversampled black women, we compared ER-borderline (n = 217) to ER-positive (n = 1885) and ER-negative (n = 757) tumors. PAM50 subtype and risk of recurrence score (ROR-PT, incorporates subtype, proliferation, tumor size) were measured. Relative frequency differences (RFD) were estimated using multivariable linear regression. Disease-free interval (DFI) was evaluated by ER category and endocrine therapy receipt, overall and by race, using Kaplan Meier and Cox models. Statistical tests were two-sided. Results: ER-borderlines were more frequently basal-like (RFD = +37.7%, 95% confidence interval [CI] = 27.1% to 48.4%) and high ROR-PT (RFD = +52.4%, 95% CI = 36.8% to 68.0%) relative to ER-positives. Having a high ROR-PT ER-borderline tumor was statistically significantly associated with black race (RFD = +26.2%, 95% CI = 9.0% to 43.3%). Compared to ER-positives, DFI of ER-borderlines treated with endocrine therapy was poorer but not statistically significantly different (hazard ratio [HR] = 2.03, 95% CI = 0.89% to 4.65%), whereas DFI was statistically significantly worse for ER-borderlines without endocrine therapy (HR = 3.33, 95% CI = 1.84% to 6.02%). However, black women with ER-borderline had worse DFI compared to ER-positives, even when treated with endocrine therapy (HR = 2.77, 95% CI = 1.09% to 7.04%). Conclusions: ER-borderline tumors were genomically heterogeneous, with survival outcomes that differed by endocrine therapy receipt and race. Black race predicted high-risk ER-borderlines and may be associated with poorer endocrine therapy response

Integrating Biology and Access to Care in Addressing Breast Cancer Disparities: 25 Years’ Research Experience in the Carolina Breast Cancer Study

Purpose of Review: To review research on breast cancer mortality disparities, emphasizing research conducted in the Carolina Breast Cancer Study, with a focus on challenges and opportunities for integration of tumor biology and access characteristics across the cancer care continuum. Recent Findings: Black women experience higher mortality following breast cancer diagnosis, despite lower incidence compared to white women. Biological factors, such as stage at diagnosis and breast cancer subtypes, play a role in these disparities. Simultaneously, social, behavioral, environmental, and access to care factors are important. However, integrated studies of biology and access are challenging and it is uncommon to have both data types available in the same study population. The central emphasis of phase 3 of the Carolina Breast Cancer Study, initiated in 2008, was to collect rich data on biology (including germline and tumor genomics and pathology) and health care access in a diverse study population, with the long-term goal of defining intervention opportunities to reduce disparities across the cancer care continuum. Summary: Early and ongoing research from CBCS has identified important interactions between biology and access, leading to opportunities to build greater equity. However, sample size, population-specific relationships among variables, and complexities of treatment paths along the care continuum pose important research challenges. Interdisciplinary teams, including experts in novel data integration and causal inference, are needed to address gaps in our understanding of breast cancer disparities