Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.

PURPOSE: In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence. METHODS: We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. RESULTS: Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). CONCLUSION: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.

Ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the Women's Health Initiative.

BACKGROUND: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years). METHODS: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates. RESULTS: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age. CONCLUSIONS: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies.

Predicting All-Cause Mortality in Women With and Without Breast Cancer Using the Schonberg Index: A Women's Health Initiative Study.

BACKGROUND: When treating older women with breast cancer, life expectancy is an important consideration. ASCO recommends calculating 10-year mortality probabilities to inform treatment decisions. One useful tool is the Schonberg index, which predicts risk-based all-cause 10-year mortality. We investigated the use of this index in women aged ≥65 years with breast cancer in the Women's Health Initiative (WHI). METHODS: We calculated 10-year mortality risk scores for 2,549 WHI participants with breast cancer ("cases") and 2,549 age-matched breast cancer-free participants ("controls") using Schonberg index risk scoring. Risk scores were grouped into quintiles for comparisons. Risk-stratified observed mortality rates and 95% confidence intervals were compared across cases and controls. Observed 10-year mortality rates in cases and controls were also compared with Schonberg index-based predicted 10-year mortality rates. RESULTS: Compared with controls, cases were more often white (P=.005), had higher income and education levels (P<.001 for both), more often lived with their husband/partner (P<.001), scored higher on subjective health/happiness (P<.001), and needed less assistance in activities of daily living (P<.001). Participants with breast cancer had similar risk-stratified 10-year mortality rates compared with controls (34% vs 33%, respectively). Stratified results showed that cases had slightly higher mortality rates than controls in the lowest risk quintile and lower mortality rates in the 2 highest risk quintiles. Observed mortality rates in cases and controls were similar to Schonberg index-predicted mortality, with model c-indexes of 0.71 and 0.76, respectively. CONCLUSIONS: Among women aged ≥65 years with incident breast cancer, the Schonberg index-based risk-stratified 10-year mortality rates were similar to those in women without breast cancer, demonstrating a similar performance of the index among both populations. Along with other health measures, prognostic indexes can help predict survival among older women with breast cancer and support geriatric oncology guidelines that promote using life expectancy calculation tools for shared decision-making.

Critical thermal limits and temperature-dependent walking speed may mediate coexistence between the native winter ant (Prenolepis imparis) and the invasive Argentine ant (Linepithemahumile).

Comparing the thermal tolerance and performance of native and invasive species from varying climatic origins may explain why some native and invasive species can coexist. We compared the thermal niches of an invasive and native ant species. The Argentine ant (Linepithema humile) is an invasive species that has spread to Mediterranean climates worldwide, where it is associated with losses in native arthropod biodiversity. In northern California, long-term surveys of ant biodiversity have shown that the winter ant (Prenolepis imparis) is the native species best able to coexist with Argentine ants. Both species tend hemipteran scales for food, and previous research suggests that these species' coexistence may depend on seasonal partitioning: winter ants are active primarily in the colder winter months, while Argentine ants are active primarily in the warmer months in northern California. We investigated the physiological basis of seasonal partitioning in Argentine and winter ants by a) measuring critical thermal limits, and b) comparing how ant walking speed varies with temperature. While both species had similar CTmax values, we found differences between the two species' critical thermal minima that may allow winter ants to remain functional at ecologically relevant temperatures between 0 and 2.5 °C. We also found that winter ants' walking speeds are significantly less temperature-dependent than those of Argentine ants. Winter ants walk faster than Argentine ants at low temperatures, which may allow the winter ants to remain active and forage at lower winter temperatures. These results suggest that partitioning based on differences in temperature tolerance promotes the winter ant's continued occupation of areas invaded by the Argentine ant.

Cardiometabolic risk factors, physical activity, and postmenopausal breast cancer mortality: results from the Women's Health Initiative.

BACKGROUND: Higher physical activity levels are associated with lower breast cancer-specific mortality. In addition, the metabolic syndrome is associated with higher breast cancer-specific mortality. Whether the physical activity association with breast cancer mortality is modified by number of metabolic syndrome components (cardiometabolic risk factors) in postmenopausal women with early-stage breast cancer remains unknown. METHODS: Cardiovascular risk factors included high waist circumference, hypertension, high cholesterol, and diabetes. Breast cancers were verified by medical record review. Mortality finding were enhanced by serial National Death Index queries. Cox proportional hazards regression models were used to estimate associations between baseline physical activity and subsequent breast cancer-specific and overall mortality following breast cancer diagnosis in Women's Health Initiative participants. These associations were examined after stratifying by cardiometabolic risk factor group. RESULTS: Among 161,308 Women's Health Initiative (WHI) participants, 8543 breast cancers occurred after 9.5 years (median) follow-up in women, additionally with information on cardiometabolic risk factors and physical activity at entry. In multi-variable analyses, as measured from cancer diagnosis, higher physical activity levels were associated with lower all-cause mortality risk (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.78-0.95, trend P < 0.001) but not with breast cancer-specific mortality (HR 0.85, 95% CI 0.70 to 1.04, trend P = 0.09). The physical activity and all-cause mortality association was not significantly modified by cardiometabolic risk factor number. CONCLUSIONS: Among women with early-stage breast cancer, although higher antecedent physical activity was associated with lower risk of all-cause mortality, the association did not differ by cardiometabolic risk factor number.

Metabolic syndrome risk components and mortality after triple-negative breast cancer diagnosis in postmenopausal women in the Women's Health Initiative.

BACKGROUND: Triple-negative breast cancer (TNBC) has a high recurrence risk and poor clinical outcomes. Associations between metabolic syndrome (MetS) risk components and mortality in postmenopausal women with TNBC were examined in the Women's Health Initiative. METHODS: Five hundred forty-four postmenopausal women were diagnosed with nonmetastatic TNBC. Baseline risk components included a high waist circumference (≥88 cm), high blood pressure, hypercholesterolemia, and diabetes. Groups were categorized by the number of MetS risk components: none, 1 or 2, or 3 or 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) across groups were computed with multivariable adjusted Cox models. Outcomes included breast cancer-specific mortality and breast cancer overall mortality (breast cancer followed by death from any cause). Variables in the multivariable model included age at TNBC diagnosis; race/ethnicity; income; education; clinical/observational trial status; history of oral contraceptive, hormone, and/or statin use; cancer stage; and chemotherapy and/or radiation treatment status. RESULTS: Of the 544 participants with TNBC, 33% had no MetS risk components (n = 178), 59% had 1 or 2 risk components (n = 323), and 8% had 3 or 4 risk components (n = 43). After a median follow-up from diagnosis of 8.3 years, multivariable results showed that women with 3 or 4 risk components had a nonsignificantly higher risk of breast cancer mortality (HR, 2.05; 95% CI, 0.94-4.47 trend P = .114) and a significantly higher risk of overall mortality (HR, 2.13; 95% CI, 1.22-3.71; trend P = .006) versus women with 0 risk components. CONCLUSIONS: Postmenopausal women with TNBC and 3 or 4 MetS risk components have a nonsignificantly higher breast cancer mortality risk and a significantly higher overall mortality risk, likely because of negative influences of metabolic risk factors on several causes of death.

Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative.

BACKGROUND: Insulin resistance is associated with higher all-cause and cancer-specific mortality in postmenopausal women. However, to the authors' knowledge, information regarding insulin resistance and breast cancer mortality risk is limited. Therefore, the authors examined associations between insulin resistance and breast cancer incidence and mortality in a subsample of Women's Health Initiative participants. METHODS: A total of 22,837 postmenopausal women with fasting baseline glucose and insulin levels were followed for incident breast cancer and breast cancer mortality. Breast cancers were verified by medical record review and serial National Death Index linkage-enhanced mortality findings. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR). Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) with 95% confidence intervals (95% CIs) for quartile comparisons. Outcomes included breast cancer incidence, deaths from breast cancer, and deaths after breast cancer (breast cancer followed by death from any cause). RESULTS: During a median of 19.8 years of follow-up of 1328 breast cancer cases, there were 512 deaths reported, 151 of which were from breast cancer. Breast cancer incidence was higher in women in the highest HOMA-IR quartile (HR, 1.34; 95% CI, 1.12-1.61 [P for trend = .003]). Although HOMA-IR was not found to be associated with risk of death from breast cancer (HR, 1.04; 95% CI, 0.60-1.79), women in the highest versus those in the lowest HOMA-IR quartile were at a higher risk of death after breast cancer (HR, 1.78; 95% CI, 1.32-2.39 [P for trend <.001]). CONCLUSIONS: Higher levels of insulin resistance in postmenopausal women are associated with higher breast cancer incidence and higher all-cause mortality after breast cancer.

Time to Adjuvant Radiotherapy in Breast Cancer Affects Survival: Implications for the American College of Surgeons Commission on Cancer Quality Metrics.

BACKGROUND: To optimize breast cancer care, the American College of Surgeons Commission on Cancer developed quality measures regarding receipt and timing of adjuvant radiotherapy (RT). Nationwide compliance with these measures and its impact on overall survival (OS) are evaluated herein. PATIENTS AND METHODS: Patients (n = 285,291) diagnosed with invasive breast cancer from 2004 to 2012 were identified from the National Cancer Database. Compliance with RT administration within 365 days from diagnosis was determined for patients with stage III disease with ≥ 4 positive lymph nodes post mastectomy and stage I-III disease post breast-conserving surgery (BCS). Univariate and multivariate logistic regression and Cox proportional hazard models were used to assess factors associated with compliance and OS, respectively. RESULTS: In the mastectomy cohort, 66.9% received timely RT, showing improved OS versus no RT patients (HR 0.70, 95% CI 0.67-0.73). Delayed RT patients (≥ 365 days) achieved equivalent OS to those receiving timely RT (HR 1.07, 95% CI 0.93-1.23) and superior OS to no RT patients (HR 0.74, 95% CI 0.65-0.85). In the BCS cohort, 89.4% received timely RT, showing improved OS versus no RT patients (HR 0.47, 95% CI 0.45-0.49). Delayed RT was associated with improved OS versus no RT (HR 0.64, 95% CI 0.56-0.74) and decreased OS versus timely RT (HR 1.37, 95% CI 1.19-1.58). Factors associated with noncompliance included insurance type and distance to hospital. CONCLUSIONS: Quality measure compliance with adjuvant RT improves OS, regardless of timing after mastectomy. However, timeliness does impact OS after BCS. Focus on modifiable factors to improve compliance such as access to care may lead to improved compliance and OS.

Insurance Status Predicts Survival in Women with Breast Cancer: Results of Breast and Cervical Cancer Treatment Program in California.

BACKGROUND AND PURPOSE: The Breast and Cervical Cancer Treatment Program (BCCTP) Act, passed by Congress in 2000, provides time-limited coverage to uninsured breast or cervical cancer patients. We examine survival differences between BCCTP cases and insured controls. METHODS: Stage I-III breast cancer patients, covered under California's BCCTP from 2005 to 2009 (N = 6343), were 1:1 matched with California Cancer Registry controls on age, race/ethnicity, and cancer stage. Overall and disease-specific (OS and DSS) survival were compared using multivariate regression. RESULTS: BCCTP cases were more often unmarried [odds ratio (OR) 2.47, 95% confidence interval (CI) 2.30-2.66], with poorly/undifferentiated tumors (OR 1.26, CI 1.13-1.40), classified as ER negative (OR 1.10, CI 1.02-1.20) and/or PR negative (OR 1.09, CI 1.01-1.17). Cases were more likely to undergo mastectomy (OR 1.13, CI 1.05-1.21) or no surgery (OR 1.64, CI 1.31-2.05) versus lumpectomy. Cases were also more likely to undergo radiation (OR 1.11, CI 1.03-1.19). Endocrine therapy rates were marginally lower in cases (OR 0.93, CI 0.86-1.00). OS and DSS were shorter in BCCTP cases on multivariate analysis (HR 1.29, CI 1.17-1.42 and HR 1.27, CI 1.14-1.42, respectively). When stratified by socioeconomic status (SES), cases had significantly shorter OS and DSS except in the lowest quintile. When stratified by stage, cases had significantly shorter OS and DSS, except for stage I. CONCLUSIONS: The BCCTP provides uninsured breast cancer patients with comprehensive and timely care. Although our results suggest that BCCTP delivers quality care, BCCTP patients have shorter survival rates, even after accounting for SES and stage differences. Further assistance to vulnerable populations is warranted, including longer duration of treatment coverage, and surveillance adhering to NCCN compliant surveillance programs.

Online Health Information-Seeking Among Older Women With Chronic Illness: Analysis of the Women's Health Initiative.

BACKGROUND: Understanding how older patients with chronic illnesses use the internet to obtain health information is relevant for the design of digital interventions aimed at improving the health and well-being of adults aged 65 years and older; this cohort represents the sickest, most expensive, and fastest-growing segment of the US population. OBJECTIVE: The objective of our study was to describe online health information-seeking behavior among older patients with chronic illnesses and to compare the characteristics of patients who report using the internet to obtain health information with those who do not. METHODS: The study population included 72,806 women aged 65 years and older enrolled in the Women's Health Initiative (WHI), a national cohort study, who completed a 2014 supplemental questionnaire assessing everyday technology use and internet use for researching health conditions. Comparisons were made between participants with and without a history of chronic illness and between users and nonusers of online sources for health information. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% CIs. RESULTS: Of the total, 59% (42,887/72,806) of older women used the internet for health information. Compared with women who did not use the internet to obtain health information, those who used the internet were younger (median age: 76 vs 81 years), more likely to be non-Hispanic white (90% [38,481/42,887] vs 87% [26,017/29,919]), earned a higher income (over $US 50,000: 55% [23,410/42,887] vs 33% [9991/29,919]), achieved a higher educational level (more than high school: 87% [37,493/42,887] vs 75% [22,377/29,919]), and were more likely to live with a partner (52% [22,457/42,887] vs 36% [10,759/29,919]) (all P<.001). Women with Alzheimer disease were least likely to report online health information-seeking compared to those without the disease (OR 0.41, 95% CI 0.38-0.43). In contrast, women with a recent diagnosis of cancer, within the previous 2 years (OR 1.23, 95% CI 1.11-1.36) or 2-5 years ago (OR 1.09, 95% CI 1.00-1.19), were most likely to use the internet for health information. CONCLUSIONS: Nearly 6 in 10 older women participating in the WHI reported using the internet to obtain health information. Patients recently diagnosed with cancer are more likely to be looking for health information online, even after adjustment for age, suggesting that these patients may have a greater need for digital health resources.

Chemoradiation Improves Survival Compared With Chemotherapy Alone in Unresected Nonmetastatic Gastric Cancer.

Background: Limited data are available to guide management of patients with stage I-III gastric cancer not undergoing potentially curative surgical resection. We compared survival outcomes associated with chemotherapy alone versus chemoradiation (CRT) in the treatment of nonmetastatic gastric cancer. Methods: Patients with gastric adenocarcinoma from 2004 to 2015 were identified using the National Cancer Database. Patients were excluded if they had surgery, metastatic disease, or T0, Tis, or T1a disease. Logistic regression was used to evaluate predictors of CRT use. Cox proportional hazards modeling was performed to compare overall survival (OS) between chemotherapy alone and CRT in overall and propensity score-matched cohorts. Results: We identified 4,795 patients with stage I-III gastric adenocarcinoma who did not undergo surgery, at a median follow-up of 11.8 months. A total of 3,316 patients (69.2%) received chemotherapy alone and 1,479 patients (30.8%) received CRT. Predictors of increased CRT use were age ≥65 years (odds ratio [OR] 1.68; 95% CI, 1.43-1.99; P<.001), Charlson-Deyo comorbidity score ≥2 (OR, 1.46; 95% CI, 1.18-1.81), and treatment at a community facility (OR, 1.27; 95% CI, 1.07-1.51; P=.006). Patients receiving CRT had a 2-year OS rate of 28.3% compared with 21.5% among those receiving chemotherapy. Multivariate analysis showed that CRT was associated with improved OS (hazard ratio [HR], 0.82; 95% CI, 0.77-0.89; P<.001). After propensity score matching, a persistent survival benefit was observed (HR, 0.80; 95% CI, 0.74-0.88; P<.001). Conclusions: In patients with stage I-III gastric cancer not undergoing surgical resection, CRT was associated with improved survival compared with chemotherapy alone. However, only 30.8% of patients received CRT in this setting.

Elevated risk of human papillomavirus-related second cancers in survivors of anal canal cancer.

BACKGROUND: Over the last decade, the causal link between human papillomavirus (HPV) infection and squamous cell carcinoma of the anus (SCCA) has been well described. Because HPV infection in one site is often associated with other sites of infection, it then follows that patients with SCCA may have an increased risk of additional HPV-related cancers. Identifying and targeting at-risk sites through cancer screening and surveillance may help to guide best practices. The current study sought to ascertain sites and risk of HPV-related second primary malignancies (SPMs) in survivors of SCCA. METHODS: Using population-based data from 1992 through 2012, the authors identified patients with SCCA and determined their risk of HPV-related SPMs, including anal, oral, and genital cancers. Standardized incidence ratios (SIRs), defined as observed to expected cases, were calculated to determine excess risk. RESULTS: Of 10,537 patients with SCCA, 416 developed HPV-related SPMs, which corresponded to an overall SIR of 21.5 (99% confidence interval [99% CI], 19.0-24.2). Men were found to have a higher SIR (35.8; 99% CI, 30.7-41.6) compared with women (12.8; 99% CI, 10.4-15.5). SIRs for a second SCCA were markedly higher in men (127.5; 99% CI, 108.1-149.2) compared with women (47.0; 99% CI, 34.7-62.1), whereas SIRs for oral cavity and pharyngeal cancers were elevated in men (3.1; 99% CI, 1.5-5.7) and women (4.4; 99% CI, 1.5-9.7). SIRs for sex-specific sites also were elevated, with male genital cancers having an SIR of 19.6 (99% CI, 8.7-37.6) and female genital cancers an SIR of 8.3 (99% CI, 6.1-11.0). CONCLUSIONS: Patients with index SCCA are at an increased risk of subsequent HPV-related SPMs. The elevated risk is most striking in patients with second primary SCCAs; however, the risk of second cancers also appears to be increased in other HPV-related sites. Cancer 2017;123:4013-21. © 2017 American Cancer Society.

Time to Treatment: Measuring Quality Breast Cancer Care.

BACKGROUND: To optimize breast cancer care, several organizations have crafted guidelines to define best practices for treating breast cancer. In addition to recommended therapies, 'timeliness of treatment' has been proposed as a quality metric. Our study evaluates time to surgical treatment and its effect on overall survival (OS). METHODS: The National Cancer Data Base (NCDB) was used to identify women diagnosed with invasive breast cancer between 2004 and 2012. Time from diagnosis to surgical treatment was calculated and grouped according to predetermined time intervals. Univariate and multivariate Cox proportional hazard models were used to assess patient and treatment factors related to OS. RESULTS: Overall, 420,792 patients initially treated with surgery were identified. Increased time to surgical treatment >12 weeks was associated with decreased OS [hazard ratio (HR) 1.14, 95 % confidence interval (CI) 1.09-1.20]. When stratified by pathologic stage, stage I patients treated at 8 to <12 weeks (HR 1.07, 95 % CI 1.02-1.13) and >12 weeks (HR 1.19, 95 % CI 1.11-1.28), as well as stage II patients treated at >12 weeks (HR 1.16, 95 % CI 1.08-1.25), had decreased OS compared with patients treated at <4 weeks. Other variables associated with decreased survival were treatment at a community cancer program, Medicaid or Medicare insurance, Black race, increasing age, mastectomy, moderately and poorly differentiated tumor grade, increasing T and N stage, and higher Charlson Index Group. CONCLUSION: The survival benefit of expedited time to initial surgical treatment varies by stage and appears to have the greatest impact in early-stage disease. Prior to establishing standard metrics, further quantification of the impact on patient outcomes is needed.

Rates of lymph node metastasis and survival in T1a gastric adenocarcinoma in Western populations.

BACKGROUND AND AIMS: EMR and endoscopic submucosal dissection (ESD) are widely accepted in Asia for treatment of early gastric cancer (EGC). Few studies have examined lymph node (LN) metastasis of EGC in Western populations. We sought to examine EGC and LN metastasis in a heterogeneous Western population. METHODS: Patients with surgically resected, histologically confirmed American Joint Committee on Cancer T1a gastric adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2002 to 2012. Patients were excluded if they had stage IV disease, had multiple primary cancers, or received neoadjuvant therapy. Rates of LN metastasis were calculated, and survival analyses were performed. RESULTS: Of 923 patients in the cohort, 72 (7.8%) had at least 1 positive LN on final pathology. When stratified by race, Asian/Pacific Islanders (APIs) demonstrated the lowest rate of LN metastases (n = 17/327, 5.2%), followed by Hispanics (n = 12/171, 7.0%), whites (n = 27/278, 9.7%), and blacks (n = 16/147, 10.9%). The highest rates of stage IA disease were observed in API (93.9%) and Hispanic (92.4%) patients, followed by white (89.9%) and black (87.1%) patients (P = .04). Survival analysis of T1a gastric cancer patients by race/ethnicity showed that 5-year overall survival was highest for API patients (API, 88%; Hispanic, 81%; black, 79%; and white, 77%; P < .01). CONCLUSIONS: The rate of LN metastasis in T1a gastric cancers in the United States is higher than the rates reported in Asia. Survival outcomes in T1a gastric cancers varied significantly by race, suggesting that definitive endoscopic treatment may not be appropriate for all patients in the United States.

Piwi-Interacting RNAs (piRNAs) Are Dysregulated in Renal Cell Carcinoma and Associated with Tumor Metastasis and Cancer-Specific Survival.

Piwi-interacting RNAs (piRNAs) are a distinct group of small noncoding RNAs (sncRNAs) that silence transposable genetic elements to protect genome integrity. Because of their limited expression in gonads and sequence diversity, piRNAs remain the most mysterious class of small RNAs. Studies have shown piRNAs are present in somatic cells and dysregulated in gastric, breast and liver cancers. By deep sequencing 24 frozen benign kidney and clear cell renal cell carcinoma (ccRCC) specimens and using the publically available piRNA database, we found 26,991 piRNAs present in human kidney tissue. Among 920 piRNAs that had at least two copies in one specimen, 19 were differentially expressed in benign kidney and ccRCC tissues, and 46 were associated with metastasis. Among the metastasis-related piRNAs, we found three piRNAs (piR-32051, piR-39894 and piR-43607) to be derived from the same piRNA cluster at chromosome 17. We confirmed the three selected piRNAs not to be miRNAs or miRNA-like sncRNAs. We further validated the aberrant expression of the three piRNAs in a 68-case formalin-fixed and paraffin-embedded (FFPE) ccRCC tissue cohort and showed the up-regulation of the three piRNAs to be highly associated with ccRCC metastasis, late clinical stage and poor cancer-specific survival.

Survival outcomes of metaplastic breast cancer patients: results from a US population-based analysis.

BACKGROUND: Metaplastic breast cancer (MBC) is a rare histologic subtype needing further characterization. The aim of our study was to compare MBC to infiltrating ductal carcinoma (IDC) of the breast and to identify demographic, clinicopathologic, treatment, and survival differences. METHODS: MBC and IDC patients were identified using the Surveillance, Epidemiology, and End Results (SEER) public-use data set. Disease-specific survival (DSS) differences were compared using the Kaplan-Meier method and log-rank tests. Univariate and multivariate Cox proportional hazard models were used to assess factors prognostic for DSS. To control for hormone receptor status, a subsequent planned analysis was completed for receptor-negative MBC and IDC. Lastly, a matched case-control analysis was conducted to minimize potential bias due to baseline demographic, clinical, and pathologic differences. RESULTS: The SEER data set included 1,011 MBC and 253,818 IDC patients diagnosed from 2001 to 2010. MBC patients had larger, higher grade tumors, had less frequent axillary nodal involvement, and were more likely to be treated with mastectomy. Five-year DSS rates were significantly worse for patients with MBC than for IDC patients (78 vs. 93 %, p < 0.0001) and for patients with receptor-negative MBC than receptor-negative IDC (77 vs. 85 %, p < 0.0001). The findings were confirmed on matched analysis. Prognostic factors identified on multivariate analyses included age, MBC histology, tumor grade, T stage, and axillary lymph node involvement. CONCLUSIONS: MBC patients have shorter DSS than IDC patients. Improved clinical and biological understanding of MBC may result in more effective therapy and better cancer outcomes.

A comparison of five competing lymph node staging schemes in a cohort of resectable gastric cancer patients.

BACKGROUND: New classifications for lymph node (LN) staging have recently been proposed to improve upon the UICC/AJCC N category staging convention. Ratio-based systems and logarithmic odds (LODDS) scores are two families of novel competing staging systems. We compared UICC/AJCC staging with 5 ratio and LODDS systems in predicting overall survival (OS) in patients with resected gastric cancer. METHODS: Using a large population-based dataset, we identified 12,184 nonmetastatic resectable gastric cancer patients between 1988 and 2004. We compared each subject's UICC/AJCC N stage with five novel staging schemes. We analyzed the OS for each method. Our comparison metric was the log-rank Chi squared statistic; larger Chi squared statistics indicate improvements in N stage discrimination. RESULTS: Median OS was 2.1 years (95 % CI 2.0-2.2 years), while median patient follow-up for surviving patients was 8.3 years (range, 1 month-22 years). Although all 5 staging systems were either comparable or superior to the UICC/AJCC convention, a LN ratio method outperformed others in N stage discrimination based on log-rank tests for OS. This trend was independent of the number of LNs examined. CONCLUSIONS: Novel LN staging methods have a higher degree of discrimination utility than the UICC/AJCC N convention. These methods may have a role in reducing the prognostic impact of LN count variability. Of the systems assessed, the LN ratio system that assigns greater risk attribution to cases with <16 LNs was the best classification method to predict OS in patients with resectable gastric cancer.

Survival analysis of contralateral prophylactic mastectomy: a question of selection bias.

BACKGROUND: Rates of contralateral prophylactic mastectomy (CPM) in women with breast cancer have increased, but most studies fail to show a survival benefit. We evaluated survival among CPM patients compared to patients undergoing single mastectomy (SM). METHODS: The Surveillance, Epidemiology, and End Results database was used to identify unilateral breast cancer patients who underwent mastectomy with/without CPM from 1998 to 2010. Case-control analysis was performed with CPM cases matched to SM controls on the basis of age group, race/ethnicity, extent of surgery, grade, T classification, N classification, estrogen receptor status, and propensity score. Survival analyses included Kaplan-Meier curves and univariate and multivariate proportional hazard models to determine factors associated with disease-specific (DSS) and overall survival (OS). RESULTS: A total of 26,526 CPM patients were identified. On multivariate regression analysis, increasing age, greater extent of surgery, increasing T and N stage, African American race, Hispanic ethnicity, poorly differentiated grade, and estrogen receptor negativity were associated with increased risk of death. CPM was associated with improved DSS (HR 0.86, 95 % CI 0.79-0.93) and even greater OS (HR 0.76, 95 % CI 0.71-0.81) compared with SM. Contralateral breast cancer (CBC) occurred in 1.6 % of women in the cohort. Removing CBC cases from analysis had little impact on CPM DSS (HR 0.86, 95 % CI 0.79-0.93) and OS (0.77, 95 % CI 0.72-0.82) suggesting that prevention of CBC by CPM does not explain the observed survival benefit. CONCLUSIONS: CPM rates continue to rise. The improved DSS and OS observed with CPM support selection bias. Prospective trials are needed to determine cohorts of patients most likely to benefit from CPM.

Validating a model for predicting breast cancer and nonbreast cancer death in women aged 55 years and older.

BACKGROUND: To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models. METHODS: We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics. RESULTS: When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC. CONCLUSIONS: Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model.

Explainable Machine Learning Model to Preoperatively Predict Postoperative Complications in Inpatients With Cancer Undergoing Major Operations.

PURPOSE: Preoperative prediction of postoperative complications (PCs) in inpatients with cancer is challenging. We developed an explainable machine learning (ML) model to predict PCs in a heterogenous population of inpatients with cancer undergoing same-hospitalization major operations. METHODS: Consecutive inpatients who underwent same-hospitalization operations from December 2017 to June 2021 at a single institution were retrospectively reviewed. The ML model was developed and tested using electronic health record (EHR) data to predict 30-day PCs for patients with Clavien-Dindo grade 3 or higher (CD 3+) per the CD classification system. Model performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), and calibration plots. Model explanation was performed using the Shapley additive explanations (SHAP) method at cohort and individual operation levels. RESULTS: A total of 988 operations in 827 inpatients were included. The ML model was trained using 788 operations and tested using a holdout set of 200 operations. The CD 3+ complication rates were 28.6% and 27.5% in the training and holdout test sets, respectively. Training and holdout test sets' model performance in predicting CD 3+ complications yielded an AUROC of 0.77 and 0.73 and an AUPRC of 0.56 and 0.52, respectively. Calibration plots demonstrated good reliability. The SHAP method identified features and the contributions of the features to the risk of PCs. CONCLUSION: We trained and tested an explainable ML model to predict the risk of developing PCs in patients with cancer. Using patient-specific EHR data, the ML model accurately discriminated the risk of developing CD 3+ complications and displayed top features at the individual operation and cohort level.