Assessment of Electronic Nicotine Delivery Systems With Cigarette Use and Self-reported Wheezing in the US Adult Population.

Importance: The prevalence of electronic nicotine delivery systems (ENDS) use has increased, leading to a concern about their respiratory health outcomes. It is unclear whether ENDS use increases the risk of wheezing, a common symptom of respiratory conditions. Objective: To provide an analysis of the longitudinal association between ENDS and cigarette use and self-reported wheezing among US adults. Design, Setting, and Participants: The US nationally representative Population Assessment of Tobacco and Health (PATH) Study was used. Longitudinal data for adults 18 years or older from wave 1 (2013-2014) to wave 5 (2018-2019) were analyzed. Data were analyzed from August 2021 to January 2023. Main Outcomes and Measures: The prevalence of self-reported wheezing (waves 2-5) was estimated for 6 strata of tobacco product use (never cigarette and noncurrent ENDS use, never cigarette and current ENDS use, current cigarette and noncurrent ENDS use, current cigarette and current ENDS use, former cigarette and noncurrent ENDS use, and former cigarette and current ENDS use). A generalized estimating equations framework evaluated the association between cigarette and ENDS use and self-reported wheezing at the subsequent wave. An interaction term between cigarette and ENDS use was added to estimate the association between joint cigarette and ENDS use categories and the association of ENDS within strata of cigarette use. Results: The analytical sample consisted of 17 075 US adults with a mean (SD) age of 45.4 (17) years, of whom 8922 (51%) were female and 10 242 (66%) were Non-Hispanic White. When compared with never cigarette and noncurrent ENDS use, the greatest association in reporting wheezing was for current cigarette and current ENDS use (adjusted odds ratio [AOR], 3.26; 95% CI, 2.82-3.77), which was similar to current cigarette and noncurrent ENDS use (AOR, 3.20; 95% CI, 2.91-3.51) and substantially greater than former cigarette and current ENDS use (AOR, 1.94; 95% CI, 1.57-2.41). Associations were small and not statistically significant for the odds of self-reported wheezing among never cigarette and current ENDS use when compared with never cigarette and noncurrent ENDS use (AOR, 1.20; 95% CI, 0.83-1.72), and for odds of wheezing and current cigarette and current ENDS use when compared with current cigarette and noncurrent ENDS use (AOR, 1.02; 95% CI, 0.91-1.15). Conclusions and Relevance: In this cohort study, exclusive ENDS use was not associated with an increase in the risk of self-reported wheezing. However, a small increase in risk between ENDS use and wheezing was reported by individuals who use cigarettes. This study adds to the literature about the potential health effects associated with ENDS use.

Time-varying association between cigarette and ENDS use on incident hypertension among US adults: a prospective longitudinal study.

OBJECTIVE: Electronic nicotine delivery systems (ENDS) products have emerged as the most popular alternative to combustible cigarettes. However, ENDS products contain potentially dangerous toxicants and chemical compounds, and little is known about their health effects. The aim of the present study was to examine the prospective association between cigarette and ENDS use on self-reported incident hypertension. DESIGN: Longitudinal cohort study. SETTING: Nationally representative sample of the civilian, non-institutionalised population in the USA. PARTICIPANTS: 17 539 adults aged 18 or older who participated at follow-up and had no self-reported heart condition or previous diagnosis of hypertension or high cholesterol at baseline. MEASURES: We constructed a time-varying tobacco exposure, lagged by one wave, defined as no use, exclusive established use (every day or some days) of ENDS or cigarettes, and dual use. We controlled for demographics (age, sex, race/ethnicity and household income), clinical risk factors (family history of heart attack, obesity, diabetes and binge drinking) and smoking history (cigarette pack-years). OUTCOMES: Self-reported incident hypertension diagnosis. RESULTS: The self-reported incidence of hypertension was 3.7% between wave 2 and wave 5. At baseline, 18.0% (n=5570) of respondents exclusively smoked cigarettes; 1.1% (n=336) exclusively used ENDS; and 1.7% (n=570) were dual users. In adjusted models, exclusive cigarette use was associated with an increased risk of self-reported incident hypertension compared with non-use (adjusted HR (aHR) 1.21, 95% CI 1.06 to 1.38), while exclusive ENDS use (aHR 1.00, 95% CI 0.68 to 1.47) and dual use (aHR 1.15, 95% CI 0.87 to 1.52) were not. CONCLUSIONS: We found that smoking increased the risk of self-reported hypertension, but ENDS use did not. These results highlight the importance of using prospective longitudinal data to examine the health effects of ENDS use.

Longitudinal Associations Between Exclusive and Dual Use of Electronic Nicotine Delivery Systems and Cigarettes and Self-Reported Incident Diagnosed Cardiovascular Disease Among Adults.

INTRODUCTION: The cardiovascular health effects of electronic nicotine delivery systems (ENDS) use are not well characterized, making it difficult to assess ENDS as a potential harm reduction tool for adults who use cigarettes. AIMS AND METHODS: Using waves 1-5 of the Population Assessment of Tobacco and Health Study (2013-2019), we analyzed the risk of self-reported incident diagnosed myocardial infarction (MI; 280 incident cases) and stroke (186 incident cases) associated with ENDS and/or cigarette use among adults aged 40 + using discrete time survival models. We employed a time-varying exposure lagged by one wave, defined as exclusive or dual established use of ENDS and/or cigarettes every day or some days, and controlled for demographics, clinical factors, and past smoking history. RESULTS: The analytic samples (MI = 11 031; stroke = 11 076) were predominantly female and non-Hispanic White with a mean age of 58 years. At baseline, 14.2% of respondents exclusively smoked cigarettes, 0.6% exclusively used ENDS, and 1.0% used both products. Incident MI and stroke were rare during follow-up (< 1% at each wave). Compared to no cigarette or ENDS use, exclusive cigarette use increased the risk of MI (aHR 1.99, 95% CI = 1.40-2.84) and stroke (aHR 2.26, 95% CI = 1.51-3.39), while exclusive ENDS use (MI: aHR 0.61, 95% CI = 0.12-3.04; stroke: aHR 1.74, 95% CI = 0.55-5.49) and dual use (MI: aHR 1.84, 95% CI = 0.64-5.30; stroke: aHR 1.12, 95% CI = 0.33-3.79) were not significantly associated with the risk of either outcome. CONCLUSIONS: Compared to non-use, exclusive cigarette use was associated with an increased risk of self-reported incident diagnosed cardiovascular disease over a 5-year period, while ENDS use was not associated with a statistically significant increase in the outcomes. IMPLICATIONS: Existing literature on the health effects of ENDS use has important limitations, including potential reverse causation and improper control for cigarette smoking. We accounted for these issues by using a prospective design and adjusting for current and former smoking status and cigarette pack-years. In this context, we did not find that ENDS use was associated with a statistically significant increase in self-reported incident diagnosed myocardial infarction or stroke over a 5-year period. While more studies are needed, this analysis provides an important foundation and key methodological considerations for future research on the health effects of ENDS use.

Association of Genetic Testing Results With Mortality Among Women With Breast Cancer or Ovarian Cancer.

BACKGROUND: Breast cancer and ovarian cancer patients increasingly undergo germline genetic testing. However, little is known about cancer-specific mortality among carriers of a pathogenic variant (PV) in BRCA1/2 or other genes in a population-based setting. METHODS: Georgia and California Surveillance Epidemiology and End Results (SEER) registry records were linked to clinical genetic testing results. Women were included who had stages I-IV breast cancer or ovarian cancer diagnosed in 2013-2017, received chemotherapy, and were linked to genetic testing results. Multivariable Cox proportional hazard models were used to examine the association of genetic results with cancer-specific mortality. RESULTS: 22 495 breast cancer and 4320 ovarian cancer patients were analyzed, with a median follow-up of 41 months. PVs were present in 12.7% of breast cancer patients with estrogen and/or progesterone receptor-positive, HER2-negative cancer, 9.8% with HER2-positive cancer, 16.8% with triple-negative breast cancer, and 17.2% with ovarian cancer. Among triple-negative breast cancer patients, cancer-specific mortality was lower with BRCA1 (hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.35 to 0.69) and BRCA2 PVs (HR = 0.60, 95% CI = 0.41 to 0.89), and equivalent with PVs in other genes (HR = 0.65, 95% CI = 0.37 to 1.13), vs noncarriers. Among ovarian cancer patients, cancer-specific mortality was lower with PVs in BRCA2 (HR = 0.35, 95% CI = 0.25 to 0.49) and genes other than BRCA1/2 (HR = 0.47, 95% CI = 0.32 to 0.69). No PV was associated with higher cancer-specific mortality. CONCLUSIONS: Among breast cancer and ovarian cancer patients treated with chemotherapy in the community, BRCA1/2 and other gene PV carriers had equivalent or lower short-term cancer-specific mortality than noncarriers. These results may reassure newly diagnosed patients, and longer follow-up is ongoing.

Multiple imputation with missing data indicators.

Multiple imputation is a well-established general technique for analyzing data with missing values. A convenient way to implement multiple imputation is sequential regression multiple imputation, also called chained equations multiple imputation. In this approach, we impute missing values using regression models for each variable, conditional on the other variables in the data. This approach, however, assumes that the missingness mechanism is missing at random, and it is not well-justified under not-at-random missingness without additional modification. In this paper, we describe how we can generalize the sequential regression multiple imputation imputation procedure to handle missingness not at random in the setting where missingness may depend on other variables that are also missing but not on the missing variable itself, conditioning on fully observed variables. We provide algebraic justification for several generalizations of standard sequential regression multiple imputation using Taylor series and other approximations of the target imputation distribution under missingness not at random. Resulting regression model approximations include indicators for missingness, interactions, or other functions of the missingness not at random missingness model and observed data. In a simulation study, we demonstrate that the proposed sequential regression multiple imputation modifications result in reduced bias in the final analysis compared to standard sequential regression multiple imputation, with an approximation strategy involving inclusion of an offset in the imputation model performing the best overall. The method is illustrated in a breast cancer study, where the goal is to estimate the prevalence of a specific genetic pathogenic variant.

Latent class analysis of use frequencies for multiple tobacco products in US adults.

A persistent challenge is characterizing patterns of tobacco use in terms of product combinations and frequency. Using Wave 4 (2016-17) Population Assessment of Tobacco and Health Study adult data, we conducted latent class analyses (LCA) of past 30-day frequency of use for 9 tobacco products. One-step LCA with joint multinomial logistic regression models compared sociodemographic factors between users (n = 13,716) and non-users (n = 17,457), and between latent classes of users. We accounted for survey design and weights. Our analyses identified 6 classes: in addition to non-users (C0: 75.7%), we found 5 distinct latent classes of users: daily exclusive cigarette users (C1: 15.5%); occasional cigarette and polytobacco users (C2: 3.8%); frequent e-product and occasional cigarette users (C3: 2.2%); daily smokeless tobacco (SLT) and infrequent cigarette users (C4: 2.0%); and occasional cigar users (C5: 0.8%). Compared to C1: C2 and C3 had higher odds of being male (versus female), younger (especially 18-24 versus 55 years), and having higher education; C2 had higher, while C3 and C4 had lower, odds of being a racial/ethnic minority (versus Non-Hispanic White); C4 and C5 had much higher odds of being male (versus female) and heterosexual (versus sexual minority) and having higher income; and C5 had higher odds of college or more education. We identified three classes of daily or frequent users of a primary product (cigarettes, SLT or e-products) and two classes of occasional users (cigarettes, cigars and polytobacco). Sociodemographic differences in class membership may influence tobacco-related health disparities associated with specific patterns of use.

Using multiple imputation to classify potential outcomes subgroups.

With medical tests becoming increasingly available, concerns about over-testing, over-treatment and health care cost dramatically increase. Hence, it is important to understand the influence of testing on treatment selection in general practice. Most statistical methods focus on average effects of testing on treatment decisions. However, this may be ill-advised, particularly for patient subgroups that tend not to benefit from such tests. Furthermore, missing data are common, representing large and often unaddressed threats to the validity of most statistical methods. Finally, it is often desirable to conduct analyses that can be interpreted causally. Using the Rubin Causal Model framework, we propose to classify patients into four potential outcomes subgroups, defined by whether or not a patient's treatment selection is changed by the test result and by the direction of how the test result changes treatment selection. This subgroup classification naturally captures the differential influence of medical testing on treatment selections for different patients, which can suggest targets to improve the utilization of medical tests. We can then examine patient characteristics associated with patient potential outcomes subgroup memberships. We used multiple imputation methods to simultaneously impute the missing potential outcomes as well as regular missing values. This approach can also provide estimates of many traditional causal quantities of interest. We find that explicitly incorporating causal inference assumptions into the multiple imputation process can improve the precision for some causal estimates of interest. We also find that bias can occur when the potential outcomes conditional independence assumption is violated; sensitivity analyses are proposed to assess the impact of this violation. We applied the proposed methods to examine the influence of 21-gene assay, the most commonly used genomic test in the United States, on chemotherapy selection among breast cancer patients.

Time Trends in Receipt of Germline Genetic Testing and Results for Women Diagnosed With Breast Cancer or Ovarian Cancer, 2012-2019.

PURPOSE: Genetic testing is important for breast and ovarian cancer risk reduction and treatment, yet little is known about its evolving use. METHODS: SEER records of women of age ≥ 20 years diagnosed with breast or ovarian cancer from 2013 to 2017 in California or Georgia were linked to the results of clinical germline testing through 2019. We measured testing trends, rates of variants of uncertain significance (VUS), and pathogenic variants (PVs). RESULTS: One quarter (25.2%) of 187,535 patients with breast cancer and one third (34.3%) of 14,689 patients with ovarian cancer were tested; annually, testing increased by 2%, whereas the number of genes tested increased by 28%. The prevalence of test results by gene category for breast cancer cases in 2017 were BRCA1/2, PVs 5.2%, and VUS 0.8%; breast cancer-associated genes or ovarian cancer-associated genes (ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53), PVs 3.7%, and VUS 12.0%; other actionable genes (APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL) PVs 0.6%, and VUS 0.5%; and other genes, PVs 0.3%, and VUS 2.6%. For ovarian cancer cases in 2017, the prevalence of test results were BRCA1/2, PVs 11.0%, and VUS 0.9%; breast or ovarian genes, PVs 4.0%, and VUS 12.6%; other actionable genes, PVs 0.7%, and VUS 0.4%; and other genes, PVs 0.3%, and VUS 0.6%. VUS rates doubled over time (2013 diagnoses: 11.2%; 2017 diagnoses: 26.8%), particularly for racial or ethnic minorities (47.8% Asian and 46.0% Black, v 24.6% non-Hispanic White patients; P < .001). CONCLUSION: A testing gap persists for patients with ovarian cancer (34.3% tested v nearly all recommended), whereas adding more genes widened a racial or ethnic gap in VUS results. Most PVs were in 20 breast cancer-associated genes or ovarian cancer-associated genes; testing other genes yielded mostly VUS. Quality improvement should focus on testing indicated patients rather than adding more genes.

Transitions between cigarette, ENDS and dual use in adults in the PATH study (waves 1-4): multistate transition modelling accounting for complex survey design.

INTRODUCTION: Even prior to 2018, electronic nicotine delivery systems (ENDS) began to dramatically change the landscape of tobacco products and product use patterns in the USA. METHODS: Using a Markov multistate transition model accounting for complex survey design, transition rates between never, non-current, cigarette, ENDS and dual use states were estimated for 23 253 adult participants in waves 1-4 (approximately 2013-2017) of the Population Assessment of Tobacco and Health study. We made short-term transition projections and estimated HRs for age, sex, race/ethnicity, education and income. RESULTS: Cigarette use was persistent among adults, with 89.7% (95% CI 89.1% to 90.3%) of exclusive cigarette users and 86.1% (95% CI 84.4% to 87.9%) of dual users remaining cigarette users (either exclusive or dual) after one wave. In contrast, ENDS use was less persistent, with 72.1% (95% CI 69.6% to 74.6%) of exclusive ENDS users and 50.5% (95% CI 47.8% to 53.3%) of dual users remaining ENDS users (with or without cigarettes) after one wave. Exclusive ENDS users were more likely to start cigarette use after one wave than either never users (HR 25.2; 95% CI 20.9 to 30.5) or non-current users (HR 5.0; 95% CI 4.3 to 5.8). Dual users of ENDS and cigarettes were more likely to stop using cigarettes than exclusive cigarette users (HR 1.9; 95% CI 1.6 to 2.3). Transition rates varied among sociodemographic groups. CONCLUSIONS: Multistate transition models are an effective tool for uncovering and characterising longitudinal patterns and determinants of tobacco use from complex survey data. ENDS use among US adults was less persistent than cigarette use prior to 2018.

Association of Attending Surgeon With Variation in the Receipt of Genetic Testing After Diagnosis of Breast Cancer.

Importance: Genetic testing after diagnosis of breast cancer is common, but little is known about the influence of the surgeon on the variation in testing. Objectives: To quantify and explain the association of attending surgeon with rates of genetic testing after diagnosis of breast cancer. Design, Setting, and Participants: This population-based study identified 7810 women with stages 0 to II breast cancer treated between July 1, 2013, and August 31, 2015, through the Surveillance, Epidemiology, and End Results registries for the state of Georgia, as well as Los Angeles County, California. Surveys were sent approximately 2 months after surgery. Also surveyed were 488 attending surgeons identified by the patients. Main Outcomes and Measures: The study examined the association of surgeon with variation in the receipt of genetic testing using information from patient and surgeon surveys merged to Surveillance, Epidemiology, and End Results and genetic testing data obtained from 4 laboratories. Results: In total, 5080 women (69.6%) of 7303 who were eligible (mean [SD] age, 61.4 [0.8] years) and 377 surgeons (77.3%) of 488 (mean [SD] age, 53.8 [10.7] years) responded to the survey. Approximately one-third (34.5% [1350 of 3910] of patients had an elevated risk of mutation carriage, and 27.0% (1056 of 3910) overall had genetic testing. Surgeons had practiced a mean (SE) of 20.9 (0.6) years, and 28.9% (107 of 370) treated more than 50 cases of new breast cancer per year. The odds of a patient receiving genetic testing increased more than 2-fold (odds ratio, 2.48; 95% CI, 1.85-3.31) if she saw a surgeon with an approach 1 SD above that of a surgeon with the mean test rate. Approximately one-third (34.1%) of the surgeon variation was explained by patient volume and surgeon attitudes about genetic testing and counseling. If a patient with higher pretest risk saw a surgeon at the 5th percentile of the surgeon distribution, she would have a 26.3% (95% CI, 21.9%-31.2%) probability of testing compared with 72.3% (95% CI, 66.7%-77.2%) if she saw a surgeon at the 95th percentile. Conclusions and Relevance: In this study, the attending surgeon was associated with the receipt of genetic testing after a breast cancer diagnosis. Variation in surgeon attitudes about genetic testing and counseling may explain a substantial amount of this association.

Uptake, Results, and Outcomes of Germline Multiple-Gene Sequencing After Diagnosis of Breast Cancer.

Importance: Low-cost sequencing of multiple genes is increasingly available for cancer risk assessment. Little is known about uptake or outcomes of multiple-gene sequencing after breast cancer diagnosis in community practice. Objective: To examine the effect of multiple-gene sequencing on the experience and treatment outcomes for patients with breast cancer. Design, Setting, and Participants: For this population-based retrospective cohort study, patients with breast cancer diagnosed from January 2013 to December 2015 and accrued from SEER registries across Georgia and in Los Angeles, California, were surveyed (n = 5080, response rate = 70%). Responses were merged with SEER data and results of clinical genetic tests, either BRCA1 and BRCA2 (BRCA1/2) sequencing only or including additional other genes (multiple-gene sequencing), provided by 4 laboratories. Main Outcomes and Measures: Type of testing (multiple-gene sequencing vs BRCA1/2-only sequencing), test results (negative, variant of unknown significance, or pathogenic variant), patient experiences with testing (timing of testing, who discussed results), and treatment (strength of patient consideration of, and surgeon recommendation for, prophylactic mastectomy), and prophylactic mastectomy receipt. We defined a patient subgroup with higher pretest risk of carrying a pathogenic variant according to practice guidelines. Results: Among 5026 patients (mean [SD] age, 59.9 [10.7] years), 1316 (26.2%) were linked to genetic results from any laboratory. Multiple-gene sequencing increasingly replaced BRCA1/2-only testing over time: in 2013, the rate of multiple-gene sequencing was 25.6% and BRCA1/2-only testing, 74.4%; in 2015 the rate of multiple-gene sequencing was 66.5% and BRCA1/2-only testing, 33.5%. Multiple-gene sequencing was more often ordered by genetic counselors (multiple-gene sequencing, 25.5% and BRCA1/2-only testing, 15.3%) and delayed until after surgery (multiple-gene sequencing, 32.5% and BRCA1/2-only testing, 19.9%). Multiple-gene sequencing substantially increased rate of detection of any pathogenic variant (multiple-gene sequencing: higher-risk patients, 12%; average-risk patients, 4.2% and BRCA1/2-only testing: higher-risk patients, 7.8%; average-risk patients, 2.2%) and variants of uncertain significance, especially in minorities (multiple-gene sequencing: white patients, 23.7%; black patients, 44.5%; and Asian patients, 50.9% and BRCA1/2-only testing: white patients, 2.2%; black patients, 5.6%; and Asian patients, 0%). Multiple-gene sequencing was not associated with an increase in the rate of prophylactic mastectomy use, which was highest with pathogenic variants in BRCA1/2 (BRCA1/2, 79.0%; other pathogenic variant, 37.6%; variant of uncertain significance, 30.2%; negative, 35.3%). Conclusions and Relevance: Multiple-gene sequencing rapidly replaced BRCA1/2-only testing for patients with breast cancer in the community and enabled 2-fold higher detection of clinically relevant pathogenic variants without an associated increase in prophylactic mastectomy. However, important targets for improvement in the clinical utility of multiple-gene sequencing include postsurgical delay and racial/ethnic disparity in variants of uncertain significance.

Recent Trends in Chemotherapy Use and Oncologists' Treatment Recommendations for Early-Stage Breast Cancer.

Background: There is growing concern about overtreatment of breast cancer as outcomes have improved over time. However, little is known about how chemotherapy use and oncologists' recommendations have changed in recent years. Methods: We surveyed 5080 women (70% response rate) diagnosed with breast cancer between 2013 and 2015 and accrued through two Surveillance, Epidemiology, and End Results registries (Georgia and Los Angeles) about chemotherapy receipt and their oncologists' chemotherapy recommendations. We surveyed 504 attending oncologists (60.3% response rate ) about chemotherapy recommendations in node-negative and node-positive case scenarios. We conducted descriptive statistics of chemotherapy use and patients' report of oncologists' recommendations and used a generalized linear mixed model of chemotherapy use according to time and clinical factors. All statistical tests were two-sided. Results: The analytic sample was 2926 patients with stage I-II, estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. From 2013 to 2015, keeping other factors constant, chemotherapy use was estimated to decline from 34.5% (95% confidence interval [CI] = 30.8% to 38.3%) to 21.3% (95% CI = 19.0% to 23.7%, P < .001). Estimated decline in chemotherapy use was from 26.6% (95% CI = 23.0% to 30.7%) to 14.1% (95% CI = 12.0% to 16.3%) for node-negative/micrometastasis patients and from 81.1% (95% CI = 76.6% to 85.0%) to 64.2% (95% CI = 58.6% to 69.6%) for node-positive patients. Use of the 21-gene recurrence score (RS) did not change among node-negative/micrometastasis patients, and increasing RS use in node-positive patients accounted for one-third of the chemotherapy decline. Patients' report of oncologists' recommendations for chemotherapy declined from 44.9% (95% CI = 40.2% to 49.7%) to 31.6% (95% CI = 25.9% to 37.9%), controlling for other factors. Oncologists were much more likely to order RS if patient preferences were discordant with their recommendations (67.4%, 95% CI = 61.7% to 73.0%, vs 17.5%, 95% CI = 13.1% to 22.0%, concordant), and they adjusted recommendations based on patient preferences and RS results. Conclusions: For both node-negative/micrometastasis and node-positive patients, chemotherapy receipt and oncologists' recommendations for chemotherapy declined markedly over time, without substantial change in practice guidelines. Results of ongoing trials will be essential to confirm the quality of this approach to breast cancer care.

Oncologists' influence on receipt of adjuvant chemotherapy: does it matter whom you see for treatment of curable breast cancer?

PURPOSE: We know little about whether it matters which oncologist a breast cancer patient sees with regard to receipt of chemotherapy. We examined oncologists' influence on use of recurrence score (RS) testing and chemotherapy in the community. METHODS: We identified 7810 women with stages 0-II breast cancer treated in 2013-15 through the SEER registries of Georgia and Los Angeles County. Surveys were sent 2 months post-surgery, (70% response rate, n = 5080). Patients identified their oncologists (n = 504) of whom 304 responded to surveys (60%). We conducted multi-level analyses on patients with ER-positive HER2-negative invasive disease (N = 2973) to examine oncologists' influence on variation in RS testing and chemotherapy receipt, using patient and oncologist survey responses merged to SEER data. RESULTS: Half of patients (52.8%) received RS testing and 27.7% chemotherapy. One-third (35.9%) of oncologists treated >50 new breast cancer patients annually; mean years in practice was 15.8. Oncologists explained 17% of the variation in RS testing but little of the variation in chemotherapy receipt (3%) controlling for clinical factors. Patients seeing an oncologist who was one standard deviation above the mean use of RS testing had over two-times higher odds of receiving RS (2.47, 95% CI 1.47-4.15), but a parallel estimate of the association of oncologist with the odds of receiving chemotherapy was much smaller (1.39, CI 1.03-1.88). CONCLUSIONS: Clinical algorithms have markedly reduced variation in chemotherapy use across oncologists. Oncologists' large influence on variation in RS use suggests that they variably seek tumor profiling to inform treatment decisions.

It is not just menopause: symptom clustering in the Study of Women's Health Across the Nation.

BACKGROUND: Patterns of symptom clustering in midlife women may suggest common underlying mechanisms or may identify women at risk of adverse health outcomes or, conversely, likely to experience healthy aging. This paper assesses symptom clustering in the Study of Women's Health Across the Nation (SWAN) longitudinally by stage of reproductive aging and estimates the probability of women experiencing specific symptom clusters. We also evaluate factors that influence the likelihood of specific symptom clusters and assess whether symptom clustering is associated with women's self-reported health status. METHODS: This analysis includes 3289 participants in the multiethnic SWAN cohort who provided information on 58 symptoms reflecting a broad range of physical, psychological and menopausal symptoms at baseline and 7 follow-up visits over 16 years. We conducted latent transition analyses to assess symptom clustering and to model symptomatology across the menopausal transition (pre, early peri-, late peri- and post-menopausal). Joint multinomial logistic regression models were used to identify demographic characteristics associated with premenopausal latent class membership. A partial proportional odds regression model was used to assess the association between latent class membership and self-reported health status. RESULTS: We identified six latent classes that ranged from highly symptomatic (LC1) across most measured symptoms, to moderately symptomatic across most measured symptoms (LC2), to moderately symptomatic for a subset of symptoms (vasomotor symptoms, pain, fatigue, sleep disturbances and physical health symptoms) (LC3 and LC5) with one class (LC3) including interference in life activities because of physical health symptoms, to numerous milder symptoms, dominated by fatigue and psychological symptoms (LC4), to relatively asymptomatic (LC6). In pre-menopause, 10% of women were classified in LC1, 16% in LC2, 14% in LC3 and LC4, 26% in LC5, and 20% in LC6. Intensity of vasomotor and urogenital symptoms as well as sexual desire) differed minimally by latent class. Classification into the two most symptomatic classes was strongly associated with financial strain, White race/ethnicity, obesity and smoking status. Over time, women were most likely to remain within the same latent class as they transitioned through menopause stages (range 39-76%), although some women worsened or improved. The probability of moving between classes did not differ substantially by menopausal stage. Women in the highly symptomatic classes more frequently rated their health as fair to poor compared to women in the least symptomatic class. CONCLUSION: Clear patterns of symptom clustering were present early in midlife, tended to be stable over time, and were strongly associated with self-perceived health. Notably, vasomotor symptoms tended to cluster with sleep disturbances and fatigue, were present in each of the moderate to highly symptomatic classes, but were not a defining characteristic of the symptom clusters. Clustering of midlife women by symptoms may suggest common underlying mechanisms amenable to interventions. Given that one-quarter of midlife women were highly or moderately symptomatic across all domains in the pre-menopause, addressing symptom burden in early midlife is likely critical to ameliorating risk in the most vulnerable populations.

Second Opinions From Medical Oncologists for Early-Stage Breast Cancer: Prevalence, Correlates, and Consequences.

IMPORTANCE: Advances in the evaluation and treatment of breast cancer have made the clinical decision-making context much more complex. A second opinion from a medical oncologist may facilitate decision making for women with breast cancer, yet little is known about second opinion use. OBJECTIVE: To investigate the patterns and correlates of second opinion use and the effect on chemotherapy decisions. DESIGN, SETTING, AND PARTICIPANTS: A total of 1901 women newly diagnosed with stages 0 to II breast cancer between July 2013 and September 2014 (response rate, 71.0%) were accrued through 2 population-based Surveillance, Epidemiology, and End Results registries (Georgia and Los Angeles County, California) and surveyed about their experiences with medical oncologists, decision making, and chemotherapy use. MAIN OUTCOMES AND MEASURES: Factors associated with second opinion use were evaluated using logistic regression. Also assessed was the association between second opinion and chemotherapy use, adjusting for chemotherapy indication and propensity for receiving a second opinion. Multiple imputation and weighting were used to account for missing data. RESULTS: A total of 1901 patients with stage I to II breast cancer (mean [SD] age, 61.6 [11.0] years; 1071 [56.3%] non-Hispanic white) saw any medical oncologist. Analysis of multiply imputed, weighted data (mean n = 1866) showed that 168 (9.8%) (SE, 0.74%) received a second opinion and 54 (3.2%) (SE, 0.47%) received chemotherapy from the second oncologist. Satisfaction with chemotherapy decisions was high and did not differ between those who did (mean [SD], 4.3 [0.08] on a 1- to 5-point scale) or did not (4.4 [0.03]) obtain a second opinion (P = .29). Predictors of second opinion use included college education vs less education (odds ratio [OR], 1.85; 95% CI, 1.24-2.75), frequent use of internet-based support groups (OR, 2.15; 95% CI, 1.12-4.11), an intermediate result on the 21-gene recurrence score assay (OR, 1.85; 95% CI, 1.11-3.09), and a variant of uncertain significance on hereditary cancer genetic testing (OR, 3.24; 95% CI, 1.09-9.59). After controlling for patient and tumor characteristics, second opinion use was not associated with chemotherapy receipt (OR, 1.04; 95% CI, 0.71-1.52). CONCLUSIONS AND RELEVANCE: Second opinion use was low (<10%) among patients with early-stage breast cancer, and high decision satisfaction regardless of second opinion use suggests little unmet demand. Along with educational level and use of internet support groups, uncertain results on genomic testing predicted second opinion use. Patient demand for second opinions may increase as more complex genomic tests are disseminated.

The influence of 21-gene recurrence score assay on chemotherapy use in a population-based sample of breast cancer patients.

PURPOSE: To quantify the influence of RS assay on changing chemotherapy plans in a general practice setting using causal inference methods. METHODS: We surveyed 3880 newly diagnosed breast cancer patients in Los Angeles and Georgia in 2013-14. We used inverse propensity weighting and multiple imputations to derive complete information for each patient about treatment status with and without testing. RESULTS: A half of the 1545 women eligible for testing (ER+ or PR+, HER2-, and stage I-II) received RS. We estimate that 30% (95% confidence interval (CI) 10-49%) of patients would have changed their treatment selections after RS assay, with 10% (CI 0-20%) being encouraged to undergo chemotherapy and 20% (CI 10-30%) being discouraged from chemotherapy. The subgroups whose treatment selections would be changed the most by RS were patients with positive nodes (44%; CI 24-64%), larger tumor (43% for tumor size >2 cm; CI 23-62%), or younger age (41% for <50 years, CI 23-58%). The assay was associated with a net reduction in chemotherapy use by 10% (CI 4-16%). The reduction was much greater for women with positive nodes (31%; CI 21-41%), larger tumor (30% for tumor size >2 cm; CI 22-38%), or younger age (22% for <50 years; CI 9-35%). CONCLUSION: RS substantially changed chemotherapy treatment selections with the largest influence among patients with less favorable pre-test prognosis. Whether this is optimal awaits the results of clinical trials addressing the utility of RS testing in selected subgroups.

Chemotherapy decisions and patient experience with the recurrence score assay for early-stage breast cancer.

BACKGROUND: The 21-gene recurrence score (RS) assay stratifies early-stage, estrogen receptor-positive breast cancer by recurrence risk. Few studies have examined the ways in which physicians use the RS to recommend adjuvant systemic chemotherapy or patients' experiences with testing and decision making. METHODS: This study surveyed 3880 women treated for breast cancer in 2013-2014; they were identified from the Los Angeles County and Georgia Surveillance, Epidemiology, and End Results registries (response rate, 71%). Women reported chemotherapy recommendations, the receipt of chemotherapy, testing experiences, and decision satisfaction. Registries linked the tumor data, RS, and surveys. Regression models examined factors associated with chemotherapy recommendations and receipt by the RS and subgroups. RESULTS: There were 1527 patients with stage I/II, estrogen receptor/progesterone receptor-positive, human epidermal growth factor 2-negative disease: 778 received an RS (62.6% of patients with node-negative, favorable disease, 24.3% of patients with node-negative, unfavorable disease, and 13.0% of patients with node-positive disease; P < .001). Overall, 47.2% of the patients received a recommendation against chemotherapy, and 40.5% received a recommendation for it. RS results correlated with recommendations: nearly all patients with high scores (31-100) received a chemotherapy recommendation (86.9%-96.5% across clinical subgroups), whereas the majority of the patients with low-risk results (0-18) received a recommendation against it (65.9%-78.2% across subgroups). Most patients with high RSs received chemotherapy (87.0%, 91.1%, and 100% across subgroups), whereas few patients with low scores received it (2.9%, 9.5%, and 26.6% across subgroups). There were no substantial racial/ethnic differences in testing or treatment. Women were largely satisfied with the RS and chemotherapy decisions. CONCLUSIONS: Oncologists use the RS to personalize treatment, even for those with node-positive disease. High satisfaction and an absence of disparities in testing and treatment suggest that precision-medicine advances have improved systemic breast cancer treatment. Cancer 2017;43-51. © 2016 American Cancer Society.

The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition.

CONTEXT: The relationship of reproductive hormones to vasomotor symptoms (VMS) has been incompletely explored, although an increase in such symptoms at midlife and their reduction with hormone therapy suggest a strong and direct relationship. Vasomotor symptoms are reported by 65-76% of women traversing the menopausal transition and are a primary reason for medical intervention during this life stage. OBJECTIVE: The purpose of this report was to relate longitudinal serum concentrations of the reproductive hormones estradiol (E2), FSH, testosterone (T), dehydroepiandrosterone sulfate (DHEAS), and SHBG and the free hormone indices free E2 index (FEI) and free T index (FTI) with the occurrence of VMS in women traversing the menopausal transition. DESIGN AND SETTING: The Study of Women's Health Across the Nation is a multisite, longitudinal, cohort study of the menopausal transition being conducted in community-based groups of women. PARTICIPANTS AND MAIN OUTCOME MEASURES: At baseline, 3302 menstruating women who belonged to one of five ethnic/racial groups were recruited and followed up with annual visits. Frequencies of symptoms (hot flashes, night sweats) for the prior 2 wk and measures of other covariates as well as potentially confounding variables were self-reported in the annual interview. Serum was obtained annually, on d 2-5 of a spontaneous cycle in cycling women or within 90 d of the anniversary of the baseline study visit in noncycling women and assayed for FSH, E2, T, SHBG, and DHEAS. FTI and FEI were calculated. This analysis incorporated available longitudinal data from 3293 women, excluding information collected at or after first report of hormone therapy use or hysterectomy. Data were analyzed using longitudinal marginal logistic regression models and a partial proportional odds model. RESULTS: After adjusting for age, body mass index, and other related covariates, VMS prevalence increased with higher (log)FSH concentrations, and the increase was greater when blood was drawn more than 5 d after menses began. FSH concentrations were positively associated with the frequency of either hot flashes or night sweats, and higher FSH concentrations were associated with greater odds of reporting more frequent symptoms. Vasomotor symptom prevalence decreased with higher (log)E2, (sqrt)SHBG, and (log)FEI but only when these hormone values were modeled independently of (log)FSH values and the specimens were obtained outside the d 2-5 window. When modeled simultaneously with (log)FSH, (log)E2, (sqrt)SHBG, and (log)FEI were no longer significantly associated with symptom prevalence. (Cubic root)T and (sqrt)DHEAS concentrations and (log)FTI were not associated with the prevalence of VMS. CONCLUSIONS: Annual serum FSH concentrations, but not E2, T, DHEAS, FTI, or FEI when collectively modeled longitudinally, are associated with both the prevalence and frequency of VMS in women at midlife.

Change in estradiol and follicle-stimulating hormone across the early menopausal transition: effects of ethnicity and age.

Serum reproductive hormone concentrations were measured longitudinally in a community-based, multiethnic population of midlife women to assess whether ethnic differences exist in the patterns of change in estradiol (E2) and FSH and, if so, whether these differences are explained by host characteristics. We studied 3257 participants from seven clinical sites in the Study of Women's Health Across the Nation (SWAN) who were aged 42-52 yr at baseline and self-identified as African American (28.2%), Caucasian (47.1%), Chinese (7.7%), Hispanic (8.4%), or Japanese (8.6%). E2 and FSH were assayed in serum collected primarily in the early follicular phase of a spontaneous menstrual cycle in three consecutive annual visits. The primary explanatory variables included in repeated-measures regression analyses were race/ethnicity, menopausal status, age, body mass index (BMI), day of the cycle, smoking, parity, socioeconomic status, study site, and the self-report of diabetes at baseline. At the baseline visit, 46.2% of the women were classified as being early perimenopausal, with the remaining being premenopausal. By the second follow-up visit, 5.5% of the women in that cohort were postmenopausal, 66.8% were early perimenopausal, 8.3% were late perimenopausal, and 19.4% remained premenopausal. Serum E2 concentrations decreased significantly with age, with a steeper decline at higher ages. FSH concentrations increased significantly with age, with a steeper increase at higher ages. Similar patterns in the decline of E2 and the increase in FSH with age were found across ethnic groups, but the levels of these hormones differed by race/ethnicity. Specifically, over time, Chinese and Japanese women had lower E2 concentrations but similar FSH levels, compared with Caucasian women, and African American women had higher FSH concentrations but comparable E2 levels with those of Caucasian women. These ethnic differences in E2 and FSH were independent of menopausal status. The effect of BMI on serum E2 and FSH levels varied by menopausal status. Increasing BMI was associated with decreasing concentrations of E2 among premenopausal and early perimenopausal women but was associated with increasing concentrations of E2 among late perimenopausal and postmenopausal women. Increasing BMI was associated with decreasing concentrations of FSH, with the effect of BMI becoming larger as women transitioned through menopause. We conclude that serum E2 levels decrease and FSH concentrations increase with increasing age in midlife women, that ethnic differences in E2 over time differ from ethnic differences in FSH and suggest ethnic differences in the pituitary-ovarian relationship, and that the effect of BMI on E2 and FSH concentrations varies by menopausal status.

Urinary incontinence predictors and life impact in ethnically diverse perimenopausal women.

OBJECTIVE: To document prevalence of mild, moderate, and severe urinary incontinence among ethnically diverse perimenopausal women, identify risk factors, and assess the effect of severity on women's daily lives using treatment seeking, bother, and nighttime voiding as indicators. METHODS: Baseline data from the longitudinal cohort of the Study of Women's Health Across the Nation, a prospective, multiethnic, multisite study of the natural history of menopausal transition was used (n = 3302). Interview and self-completed questionnaires assessed most variables of interest. Body mass index and diabetes mellitus were measured clinically. Incontinence severity was derived by multiplying frequency by volume leaked. Risk factors and effect on treatment seeking, bother, and nighttime voiding were assessed by the construction of multiple logistic regression models for each ethnic group and the total population. RESULTS: Mean age was 46.4 years. Incontinence prevalence was 57%, with nearly 15% categorized as moderate and 10% as severe. Biologic factors constituted the most important risk for severity, specifically perimenopausal compared with premenepausal status (odds ratio [OR] 1.35), body mass index (OR 1.04), diabetes mellitus (OR 1.55), and current smoking (OR 1.38). Nonwhite groups had lower risk, but the relationship of ethnicity is complex. Severity was associated with likelihood of discussing with a health care provider, with bothersomeness, and with likelihood of nighttime voiding. CONCLUSION: Large numbers of perimenopausal women experience urinary incontinence with 25% wearing protection or changing undergarments on several days per week. Mutable factors predicting severity included body mass index and current smoking.