George Luta

Randomized Noninferiority Trial of Telephone Versus In-Person Genetic Counseling for Hereditary Breast and Ovarian Cancer

PURPOSE Although guidelines recommend in-person counseling before BRCA1/BRCA2 gene testing, genetic counseling is increasingly offered by telephone. As genomic testing becomes more common, evaluating alternative delivery approaches becomes increasingly salient. We tested whether telephone delivery of BRCA1/2 genetic counseling was noninferior to in-person delivery. PATIENTS AND METHODS Participants (women age 21 to 85 years who did not have newly diagnosed or metastatic cancer and lived within a study site catchment area) were randomly assigned to usual care (UC; n = 334) or telephone counseling (TC; n = 335). UC participants received in-person pre- and post-test counseling; TC participants completed all counseling by telephone. Primary outcomes were knowledge, satisfaction, decision conflict, distress, and quality of life; secondary outcomes were equivalence of BRCA1/2 test uptake and costs of delivering TC versus UC. RESULTS TC was noninferior to UC on all primary outcomes. At 2 weeks after pretest counseling, knowledge (d = 0.03; lower bound of 97.5% CI, -0.61), perceived stress (d = -0.12; upper bound of 97.5% CI, 0.21), and satisfaction (d = -0.16; lower bound of 97.5% CI, -0.70) had group differences and confidence intervals that did not cross their 1-point noninferiority limits. Decision conflict (d = 1.1; upper bound of 97.5% CI, 3.3) and cancer distress (d = -1.6; upper bound of 97.5% CI, 0.27) did not cross their 4-point noninferiority limit. Results were comparable at 3 months. TC was not equivalent to UC on BRCA1/2 test uptake (UC, 90.1%; TC, 84.2%). TC yielded cost savings of

Effectiveness of Primary Androgen-Deprivation Therapy for Clinically Localized Prostate Cancer

114 per patient. CONCLUSION Genetic counseling can be effectively and efficiently delivered via telephone to increase access and decrease costs.

Long-Term Psychosocial Outcomes of BRCA1/BRCA2 Testing: Differences across Affected Status and Risk-Reducing Surgery Choice

PURPOSE Primary androgen-deprivation therapy (PADT) is often used to treat clinically localized prostate cancer, but its effects on cause-specific and overall mortality have not been established. Given the widespread use of PADT and the potential risks of serious adverse effects, accurate mortality data are needed to inform treatment decisions. METHODS We conducted a retrospective cohort study using comprehensive utilization and cancer registry data from three integrated health plans. All men were newly diagnosed with clinically localized prostate cancer. Men who were diagnosed between 1995 and 2008, were not treated with curative intent therapy, and received follow-up through December 2010 were included in the study (n = 15,170). We examined all-cause and prostate cancer-specific mortality as our main outcomes. We used Cox proportional hazards models with and without propensity score analysis. RESULTS Overall, PADT was associated with neither a risk of all-cause mortality (hazard ratio [HR], 1.04; 95% CI, 0.97 to 1.11) nor prostate-cancer-specific mortality (HR, 1.03; 95% CI, 0.89 to 1.19) after adjusting for all sociodemographic and clinical characteristics. PADT was associated with decreased risk of all-cause mortality but not prostate-cancer-specific mortality. PADT was associated with decreased risk of all-cause mortality only among the subgroup of men with a high risk of cancer progression (HR, 0.88; 95% CI, 0.78 to 0.97). CONCLUSION We found no mortality benefit from PADT compared with no PADT for most men with clinically localized prostate cancer who did not receive curative intent therapy. Men with higher-risk disease may derive a small clinical benefit from PADT. Our study provides the best available contemporary evidence on the lack of survival benefit from PADT for most men with clinically localized prostate cancer.

Parental smoking exposure and adolescent smoking trajectories.

Background: Numerous studies have documented the short-term impact of BRCA1/BRCA2 (BRCA1/2) testing; however, little research has examined the long-term impact of testing. We conducted the first long-term prospective study of psychosocial outcomes in a U.S. sample of women who had BRCA1/2 testing. Methods: Participants were 464 women who underwent genetic testing for BRCA1/2 mutations. Prior to testing, we measured sociodemographics, clinical variables, and cancer specific and general distress. At long-term follow-up (Median = 5.0 years; Range = 3.4–9.1 years), we assessed cancer-specific and genetic testing distress, perceived stress, and perceived cancer risk. We evaluated the impact of BRCA1/2 test result and risk-reducing surgery on long-term psychosocial outcomes. Results: Among participants who had been affected with breast or ovarian cancer, BRCA1/2 carriers reported higher genetic testing distress (β = 0.41, P < 0.0001), uncertainty (β = 0.18, P < 0.0001), and perceived stress (β = 0.17, P = 0.005) compared with women who received negative (i.e., uninformative) results. Among women unaffected with breast/ovarian cancer, BRCA1/2 carriers reported higher genetic testing distress (β = 0.39, P < 0.0001) and lower positive testing experiences (β = 0.25, P = 0.008) than women with negative results. Receipt of risk-reducing surgery was associated with lower perceived cancer risk (P < 0.0001). Conclusions: In this first prospective long-term study in a U.S. sample, we found modestly increased distress in BRCA1/2 carriers compared with women who received uninformative or negative test results. Despite this modest increase in distress, we found no evidence of clinically significant dysfunction. Impact: Although a positive BRCA1/2 result remains salient among carriers years after testing, testing does not seem to impact long-term psychologic dysfunction. Cancer Epidemiol Biomarkers Prev; 21(3); 445–55. ©2012 AACR.

Long-Term Disease-Specific Functioning Among Prostate Cancer Survivors and Noncancer Controls in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

OBJECTIVE: In a multigenerational study of smoking risk, the objective was to investigate the intergenerational transmission of smoking by examining if exposure to parental smoking and nicotine dependence predicts prospective smoking trajectories among adolescent offspring. METHODS: Adolescents (n = 406) ages 12 to 17 and a parent completed baseline interviews (2001–2004), and adolescents completed up to 2 follow-up interviews 1 and 5 years later. Baseline interviews gathered detailed information on parental smoking history, including timing and duration, current smoking, and nicotine dependence. Adolescent smoking and nicotine dependence were assessed at each time point. Latent Class Growth Analysis identified prospective smoking trajectory classes from adolescence into young adulthood. Logistic regression was used to examine relationships between parental smoking and adolescent smoking trajectories. RESULTS: Four adolescent smoking trajectory classes were identified: early regular smokers (6%), early experimenters (23%), late experimenters (41%), and nonsmokers (30%). Adolescents with parents who were nicotine-dependent smokers at baseline were more likely to be early regular smokers (odds ratio 1.18, 95% confidence interval 1.05–1.33) and early experimenters (odds ratio 1.04, 95% confidence interval 1.04–1.25) with each additional year of previous exposure to parental smoking. Parents’ current non-nicotine–dependent and former smoking were not associated with adolescent smoking trajectories. CONCLUSIONS: Exposure to parental nicotine dependence is a critical factor influencing intergenerational transmission of smoking. Adolescents with nicotine-dependent parents are susceptible to more intense smoking patterns and this risk increases with longer duration of exposure. Research is needed to optimize interventions to help nicotine-dependent parents quit smoking early in their children’s lifetime to reduce these risks.

Interest in Genetic Testing for Modest Changes in Breast Cancer Risk: Implications for SNP Testing

PURPOSE Within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), we assessed the long-term disease-specific functioning among prostate cancer (PCa) survivors versus noncancer controls, the impact of trial arm (screening/usual care) on functioning, and the effect of treatment modality on functioning. PATIENTS AND METHODS PCa survivors (n = 529), 5 to 10 years postdiagnosis, were frequency-matched to noncancer controls (n = 514) for race, screening center, year of enrollment, and trial arm. Participants completed a telephone interview regarding PCa-specific symptomatology. Weights accounted for patient selection from the five PLCO screening centers. Propensity-score methods were used to balance groups of interest with respect to demographic and medical characteristics. RESULTS Weighted linear regression analyses revealed poorer sexual and urinary function among PCa survivors compared with noncancer controls (P < .001). Trial arm was not significantly related to any outcome (P > .31). Compared with radical prostatectomy patients (n = 201), radiation-therapy patients (n = 110) reported better sexual (P < .05) and urinary (P < .001) functioning but poorer bowel outcomes (P < .05). Survivors who received treatment combinations including androgen deprivation (n = 207) reported significantly poorer hormone-related symptoms compared with radical prostatectomy patients (P < .05). CONCLUSION This study demonstrated the persistence of clinically significant, long-term PCa treatment-related sexual and urinary adverse effects up to 10 years postdiagnosis. To our knowledge, this was the first comparison of prostate-related dysfunction among screened survivors versus screened noncancer controls and indicated that these long-term problems were attributable to PCa treatment and not to aging or comorbidities. Finally, differences in long-term adverse effects between treatment modalities are particularly relevant for patients and clinicians when making treatment decisions.

Frailty and Adherence to Adjuvant Hormonal Therapy in Older Women With Breast Cancer: CALGB Protocol 369901

Background: Advances in genomics may eventually lead to ‘personalized genetic medicine,’ yet the clinical utility of predictive testing for modest changes in risk is unclear. We explored interest in genetic testing for genes related to modest changes in breast cancer risk in women at moderate to high risk for breast cancer. Methods: Women (n = 105) with a negative breast biopsy and ≧1 relative with breast or ovarian cancer completed telephone surveys. We measured demographic and psychosocial variables and, following presentation of hypothetical scenarios of genetic tests for lower-penetrance breast cancer gene mutations, assessed interest in willingness to pay for and comprehension of test results. We used logistic regression models with generalized estimating equations to evaluate combinations of risk level, cost and behavioral modifiers. Results: Many women (77%) reported ‘definite’ interest in genetic testing, with greater interest in tests that conveyed more risk and cost less. Behavioral modifiers of risk (taking a vitamin; diet/exercise), having a regular physician, greater perceived benefits of genetic testing, and greater cancer worry also influenced interest. Most participants (63%) did not understand relative vs. absolute risk. Women with less understanding reported more cancer worry and greater willingness to pay for testing. Conclusion: Interest in genetic testing for mutations related to modest changes in risk was high, modified by both test and psychosocial factors. Findings highlight the need for education about benefits and risks of testing for mutations that convey modest changes in risk, particularly given the current lack of clinical validity/utility and availability of direct-to-consumer genetic testing.

The significance of TNFAIP8 in prostate cancer response to radiation and docetaxel and disease recurrence

PURPOSE Most patients with breast cancer age ≥ 65 years (ie, older patients) are eligible for adjuvant hormonal therapy, but use is not universal. We examined the influence of frailty on hormonal therapy noninitiation and discontinuation. PATIENTS AND METHODS A prospective cohort of 1,288 older women diagnosed with invasive, nonmetastatic breast cancer recruited from 78 sites from 2004 to 2011 were included (1,062 had estrogen receptor-positive tumors). Interviews were conducted at baseline, 6 months, and annually for up to 7 years to collect sociodemographic, health care, and psychosocial data. Hormonal initiation was defined from records and discontinuation from self-report. Baseline frailty was measured using a previously validated 35-item scale and grouped as prefrail or frail versus robust. Logistic regression and proportional hazards models were used to assess factors associated with noninitiation and discontinuation, respectively. RESULTS Most women (76.4%) were robust. Noninitiation of hormonal therapy was low (14%), but in prefrail or frail (v robust) women the odds of noninitiation were 1.63 times as high (95% CI, 1.11 to 2.40; P = .013) after covariate adjustment. Nonwhites (v whites) had higher odds of noninitiation (odds ratio, 1.71; 95% CI, 1.04 to 2.80; P = .033) after covariate adjustment. Among initiators, the 5-year continuation probability was 48.5%. After adjustment, the risk of discontinuation was higher with increasing age (P = .005) and lower for stage ≥ IIB (v stage I) disease (P = .003). CONCLUSION Frailty is associated with noninitiation of hormonal therapy, but it does not seem to be a major predictor of early discontinuation in older patients.

Randomized Controlled Trial of a Psychosocial Telephone Counseling Intervention in BRCA1 and BRCA2 Mutation Carriers

TNFAIP8 is a NF‐κB‐inducible, oncogenic molecule. Previous “promoter array” studies have identified differential methylation and regulation of TNFAIP8 in prostate epithelial and cancer cell lines. Here we demonstrate that TNFAIP8 expression is induced by androgen in hormone‐responsive LNCaP prostate cancer cells. In athymic mice bearing hormone‐refractory PC‐3 prostate tumor xenografts, intravenous treatment with a liposomal formulation of TNFAIP8 antisense oligonucleotide (LE‐AS5) caused reduced expression of TNFAIP8 in tumor tissues, and a combination of LE‐AS5 and radiation or docetaxel treatment resulted in significant inhibition of PC‐3 tumor growth as compared to single agents. The immunohistochemical evaluation of TNFAIP8 expression revealed correlation of both cytoplasmic and nuclear TNFAIP8 overexpression with high grade prostatic adenocarcinomas, while nuclear overexpression was found to be an independent predictor of disease recurrence controlling for tumor grade. Increased nuclear TNFAIP8 expression was statistically significantly associated with a 2.44 fold (95 % confidence interval: 1.01–5.91) higher risk of prostate cancer recurrence. Mechanistically, TNFAIP8 seems to function as a scaffold (or adaptor) protein. In the antibody microarray analysis of proteins associated with the TNFAIP8 immune‐complex, we have identified Karyopherin alpha2 as a novel binding partner of nuclear TNFAIP8 in PC‐3 cells. The Ingenuity Pathway Analysis of the TNFAIP8 interacting proteins suggested that TNFAIP8 influences cancer progression pathways and networks involving integrins and matrix metalloproteinases. Taken together, present studies demonstrate that TNFAIP8 is a novel therapeutic target in prostate cancer, and indicate a potential relationship of the nuclear trafficking of TNFAIP8 with adverse outcomes in a subset of prostate cancer patients.

The curvHDR method for gating flow cytometry samples

Background: Responses following BRCA1/2 genetic testing are relevant for the comprehension of risk status and may play a role in risk management decision making. The objective of this study was to evaluate a psychosocial telephone counseling (PTC) intervention delivered to BRCA1/2 mutation carriers following standard genetic counseling (SGC). We examined the effect of the intervention on distress and the concerns related to genetic testing. Methods: This prospective randomized clinical trial included 90 BRCA1/2 mutation carriers. We measured anxiety, depression, and genetic testing distress outcomes at intervention baseline and 6 and 12 months following disclosure. We evaluated the effects of SGC versus SGC plus PTC on psychological outcomes using intention-to-treat analyses through generalized estimating equations. Results: At 6 months, PTC reduced depressive symptoms (Z = −2.25, P = 0.02) and genetic testing distress (Z = 2.18, P = 0.02) compared with SGC. Furthermore, women in the intervention condition reported less clinically significant anxiety at 6 months (χ21 = 4.11, P = 0.04) than women who received SGC. We found no differences in outcomes between the intervention groups at the 12-month follow-up. Conclusions: As an adjunct to SGC, PTC delivered following disclosure of positive BRCA1/2 test results seems to offer modest short-term benefits for distress and anxiety. These results build upon a growing literature of psychosocial interventions for BRCA1/2 carriers and, given the potential impact of affect on risk management decision making, suggest that some carriers may derive benefits from adjuncts to traditional genetic counseling. Cancer Epidemiol Biomarkers Prev; 19(3); 648–54