Melisa L. Wong

Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152).

A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.

Impact of Age and Comorbidity on Non–Small-Cell Lung Cancer Treatment in Older Veterans

PURPOSE Because comorbidity affects cancer treatment outcomes, guidelines recommend considering comorbidity when making treatment decisions in older patients with lung cancer. Yet, it is unclear whether treatment is targeted to healthier older adults who might reasonably benefit. PATIENTS AND METHODS Receipt of first-line guideline-recommended treatment was assessed for 20,511 veterans age ≥ 65 years with non-small-cell lung cancer (NSCLC) in the Veterans Affairs (VA) Central Cancer Registry from 2003 to 2008. Patients were stratified by age (65 to 74, 75 to 84, ≥ 85 years), Charlson comorbidity index score (0, 1 to 3, ≥ 4), and American Joint Committee on Cancer stage (I to II, IIIA to IIIB, IIIB with malignant effusion to IV). Comorbidity and patient characteristics were obtained from VA claims and registry data. Multivariate analysis identified predictors of receipt of guideline-recommended treatment. RESULTS In all, 51% of patients with local, 35% with regional, and 27% with metastatic disease received guideline-recommended treatment. Treatment rates decreased more with advancing age than with worsening comorbidity for all stages, such that older patients with no comorbidity had lower rates than younger patients with severe comorbidity. For example, 50% of patients with local disease age 75 to 84 years with no comorbidity received surgery compared with 57% of patients age 65 to 74 years with severe comorbidity (P < .001). In multivariate analysis, age and histology remained strong negative predictors of treatment for all stages, whereas comorbidity and nonclinical factors had a minor effect. CONCLUSION Advancing age is a much stronger negative predictor of treatment receipt among older veterans with NSCLC than comorbidity. Individualized decisions that go beyond age and include comorbidity are needed to better target NSCLC treatments to older patients who may reasonably benefit.

Posttraumatic growth and adverse long-term effects of parental cancer in children.

This study examined the long-term impact of parental cancer during childhood. Nineteen female and 8 male adults who had a parent with terminal or nonterminal cancer during childhood participated in face-to-face interviews during which they discussed how their parents cancer affected their lives. Their interview responses were transcribed and analyzed using a constant comparative method of analysis. Posttraumatic growth experiences were reported by 44% of participants, and 59% reported adverse consequences. Future research should examine ways to identify factors that can help affected children experience posttraumatic growth while minimizing the adverse consequences of having a parent with cancer.

Chemotherapy-related cognitive impairment in older patients with cancer

Chemotherapy-related cognitive impairment (CRCI) can occur during or after chemotherapy and represents a concern for many patients with cancer. Among older patients with cancer, in whom there is little clinical trial evidence examining side effects like CRCI, many unanswered questions remain regarding risk for and resulting adverse outcomes from CRCI. Given the rising incidence of cancer with age, CRCI is of particular concern for older patients with cancer who receive treatment. Therefore, research related to CRCI in older patients with cancers is a high priority. In this manuscript, we discuss current gaps in research highlighting the lack of clinical studies of CRCI in older adults, the complex mechanisms of CRCI, and the challenges in measuring cognitive impairment in older patients with cancer. Although we focus on CRCI, we also discuss cognitive impairment related to cancer itself and other treatment modalities. We highlight several research priorities to improve the study of CRCI in older patients with cancer.

Enrollment Trends and Disparity Among Patients With Lung Cancer in National Clinical Trials, 1990 to 2012

Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients ≥ 70 years of age with non-small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P = .020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 ( P = .714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P = .020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non-small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer.

Children’s Perceived Social Support After a Parent Is Diagnosed with Cancer

This study examined perceived social support among children of parents diagnosed with cancer. Twenty-nine participants, ages 18–38, who had been children when one of their parents was diagnosed with cancer provided demographic information and participated in an interview about the impact of their parent’s illness on their lives. Five common themes characterized participants’ perceived social support received during their parent’s illness: (a) listening and understanding; (b) encouragement and reassurance; (c) tangible assistance; (d) communication about cancer and treatment; and (e) engaging in normal life experiences. Depending on the circumstances, however, a given type of social support was perceived to be helpful to some, while perceived by others as ineffective or detrimental. Differences in respondents’ perceptions of the effects of specific forms of received social support speak to the need for individualized support for children of cancer patients based upon each child’s specific needs and circumstances.

Understanding cognition in older patients with cancer

Cancer and neurocognitive disorders, such as dementia and delirium, are common and serious diseases in the elderly that are accompanied by high degree of morbidity and mortality. Furthermore, evidence supports the under-diagnosis of both dementia and delirium in older adults. Complex questions exist regarding the interaction of dementia and delirium with cancer, beginning with guidelines on how best measure disease severity, the optimal screening test for either disorder, the appropriate level of intervention in the setting of abnormal findings, and strategies aimed at preventing the development or progression of either process. Ethical concerns emerge in the research setting, pertaining to the detection of cognitive dysfunction in participants, validity of consent, disclosure of abnormal results if screening is pursued, and recommended level of intervention by investigators. Furthermore, understanding the ways in which comorbid cognitive dysfunction and cancer impact both cancer and non-cancer-related outcomes is essential in guiding treatment decisions. In the following article, we will discuss what is presently known of the interactions of pre-existing cognitive impairment and delirium with cancer. We will also discuss identified deficits in our knowledge base, and propose ways in which innovative research may address these gaps.

Incidence of Non–Small-Cell Lung Cancer among California Hispanics According to Neighborhood Socioeconomic Status

Introduction: Lung cancer incidence is associated with markers of lower socioeconomic status (SES) in whites, blacks, and Asians but with markers of higher SES in Hispanics. The magnitude and etiology of this positive gradient in Hispanics remain undefined. We examined non–small-cell lung cancer (NSCLC) incidence and ever-smoking rates among California Hispanics according to measures of SES. Methods: We computed neighborhood (n)SES-specific incidence rates by sex and race or ethnicity for 74,179 NSCLC cases in the California Cancer Registry, 1998–2002. Associations between nSES and NSCLC incidence were examined, using incidence rate ratios and linear trend tests, and stratified by age, stage, and histology. Ever-smoking rates among Hispanics were obtained from California Health Interview Survey 2001 data, and odds ratios for ever-smoking were calculated for measures of SES and acculturation. Results: Compared with the lowest nSES quintile, the NSCLC incidence in the highest quintile was 1.86 and 1.18 times higher for Hispanic women and men, respectively. The positive nSES gradients remained significant for all ages, stages, and nonsquamous histologies in women, and only for older age, local or regional stages, and adenocarcinoma histology in men. Ever-smoking rates were associated with English-speaking households and U.S.-born status for Hispanic women and low education and U.S.-born status for Hispanic men. Conclusions: For California Hispanics, higher nSES was strongly associated with increased NSCLC incidence in women, but weakly associated in men, and ever-smoking rates were strongly correlated with increased acculturation. This finding may portend an increasing burden of NSCLC in Hispanic women, given future trends in acculturation and SES.

Clinician Factors Associated With Prostate-Specific Antigen Screening in Older Veterans With Limited Life Expectancy

IMPORTANCE Despite guidelines recommending against prostate-specific antigen (PSA) screening in elderly men with limited life expectancy, PSA screening remains common. OBJECTIVE To identify clinician characteristics associated with PSA screening rates in older veterans stratified by life expectancy. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 826 286 veterans 65 years or older eligible for PSA screening who had VA laboratory tests performed in 2011 in the VA health care system. MAIN OUTCOMES AND MEASURES The primary outcome was the percentage of men with a screening PSA test in 2011. Limited life expectancy was defined as age of at least 85 years with Charlson comorbidity score of 1 or greater or age of at least 65 years with Charlson comorbidity score of 4 or greater. Primary predictors were clinician characteristics including degree-training level, specialty, age, and sex. We performed log-linear Poisson regression models for the association between each clinician characteristic and PSA screening stratified by patient life expectancy and adjusted for patient demographics and clinician clustering. RESULTS In 2011, 466 017 (56%) of older veterans received PSA screening, including 39% of the 203 717 men with limited life expectancy. After adjusting for patient demographics, higher PSA screening rates in patients with limited life expectancy was associated with having a clinician who was an older man and was no longer in training. The PSA screening rates ranged from 27% for men with a physician trainee to 42% for men with an attending physician (P < .001); 22% for men with a geriatrician to 82% for men with a urologist as their clinician (P < .001); 29% for men with a clinician 35 years or younger to 41% for those with a clinician 56 years or older (P < .001); and 38% for men with a female clinician older than 55 years vs 43% for men with a male clinician older than 55 years (P < .001). CONCLUSIONS AND RELEVANCE More than one-third of men with limited life expectancy received PSA screening. Men whose clinician was a physician trainee had substantially lower PSA screening rates than those with an attending physician, nurse practitioner, or physician assistant. Interventions to reduce PSA screening rates in older men with limited life expectancy should be designed and targeted to high-screening clinicians- older male, nontrainee clinicians-for greatest impact.

Time-to-Treatment-Failure and Related Outcomes Among 1000+ Advanced Non–Small Cell Lung Cancer Patients: Comparisons Between Older Versus Younger Patients (Alliance A151711)

Introduction: Time‐to‐treatment‐failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. Methods: Pooled analyses were conducted with first‐line chemotherapy trials for advanced NSCLC (CALGB 9730, 30203, and 30801). Comparisons among patients who were 65 years and older and 70 years and older were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. Results: Among 1006 patients, 460 (46%) were older than 65 years of age. One hundred forty‐five older patients (32% of this age cohort) completed all six planned chemotherapy cycles as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval: 2.7– 3.2) in older patients and 3 months (95% confidence interval: 2.9–3.5) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age‐based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cutpoint of 70+ years showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. Conclusions: TTF was comparable between older and younger patients; but different, age‐based, and potentially modifiable reasons account for it.