Machine Learning-Driven Phenogrouping and Cardiorespiratory Fitness Response in Metastatic Breast Cancer.

PURPOSE: The magnitude of cardiorespiratory fitness (CRF) impairment during anticancer treatment and CRF response to aerobic exercise training (AT) are highly variable. The aim of this ancillary analysis was to leverage machine learning approaches to identify patients at high risk of impaired CRF and poor CRF response to AT. METHODS: We evaluated heterogeneity in CRF among 64 women with metastatic breast cancer randomly assigned to 12 weeks of highly structured AT (n = 33) or control (n = 31). Unsupervised hierarchical cluster analyses were used to identify representative variables from multidimensional prerandomization (baseline) data, and to categorize patients into mutually exclusive subgroups (ie, phenogroups). Logistic and linear regression evaluated the association between phenogroups and impaired CRF (ie, ≤16 mL O2·kg-1·min-1) and CRF response. RESULTS: Baseline CRF ranged from 10.2 to 38.8 mL O2·kg-1·min-1; CRF response ranged from -15.7 to 4.1 mL O2·kg-1·min-1. Of the n = 120 candidate baseline variables, n = 32 representative variables were identified. Patients were categorized into two phenogroups. Compared with phenogroup 1 (n = 27), phenogroup 2 (n = 37) contained a higher number of patients with none or >three lines of previous anticancer therapy for metastatic disease and had lower resting left ventricular systolic and diastolic function, cardiac output reserve, hematocrit, lymphocyte count, patient-reported outcomes, and CRF (P < .05) at baseline. Among patients allocated to AT (phenogroup 1, n = 12; 44%; phenogroup 2, n = 21; 57%), CRF response (-1.94 ± 3.80 mL O2·kg-1·min-1 v 0.70 ± 2.22 mL O2·kg-1·min-1) was blunted in phenogroup 2 compared with phenogroup 1. CONCLUSION: Phenotypic clustering identified two subgroups with unique baseline characteristics and CRF outcomes. The identification of CRF phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions among patients with cancer.

Omission of Axillary Lymph Node Dissection in Patients with Residual Nodal Disease After Neoadjuvant Chemotherapy.

BACKGROUND: Axillary management after neoadjuvant chemotherapy (NAC) is evolving but axillary lymph node dissection (ALND) remains the standard of care for patients with residual nodal disease. The results of the Alliance A011202 trial evaluating the oncologic safety of ALND omission in this cohort are pending but we hypothesize that ALND omission is already increasing. METHODS: The National Cancer Database was queried to identify patients diagnosed with cT1-3N1M0 breast cancer who underwent NAC and had residual nodal disease (ypN1mi-2) from 2012 to 2021. Temporal trends in omission of completion ALND were assessed annually. Multivariable logistic and Cox regression models were used to identify factors associated with ALND omission and overall survival (OS), respectively. RESULTS: A total of 6101 patients were included; the majority presented with cT2 disease (57%), with 69% HER2+, 23% triple-negative, and 8% hormone receptor-positive/HER2-. Overall, 34% underwent sentinel lymph node biopsy (SLNB) alone. Rates of ALND were the lowest in the last 4 years of observation. After adjustment, treatment at community centers (vs. academic) and lower pathologic nodal burden were associated with omission of ALND. ALND omission was associated with a higher unadjusted OS (5-year OS: 86% SLNB alone vs. 84% ALND; log-rank p = 0.03), however this association was not maintained after adjustment. CONCLUSIONS: Despite the impending release of the Alliance A011202 results, omission of ALND in patients with residual nodal disease after NAC is increasing. This practice appears more prominent in community centers and in patients with a lower burden of residual nodal disease. No association with OS was noted.

Germline genetic mutations in a multi-center cohort of 248 phyllodes tumors.

PURPOSE: Germline genetic mutations in women with phyllodes tumors (PT) are understudied, although some describe associations of PT with various mutations. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in women with PT. METHODS: A 6-site multi-center study of women with a PT was initiated, then expanded nationally through an online "Phyllodes Support Group." All women underwent 84-gene panel testing. We defined eligibility for testing based on select NCCN (National Comprehensive Cancer Network) criteria (v1.2022). Logistic regression was used to estimate the association of covariates with the likelihood of a P/LP variant. RESULTS: 274 women were enrolled: 164 (59.9%) through multi-center recruitment and 110 (40.1%) via online recruitment. 248 women completed testing; overall 14.1% (N = 35) had a P/LP variant, and over half (N = 19) of these individuals had a mutation in genes associated with autosomal dominant (AD) cancer conditions. The most common AD genes with a P/LP variant included CHEK2, ATM, and RAD51D. A quarter of participants (23.8%) met NCCN criteria for testing, but we found no difference in prevalence of a P/LP variant based on eligibility (p = 0.54). After adjustment, the presence of P/LP variants was not associated with age, NCCN testing eligibility, or PT type (all p > 0.05). CONCLUSION: Our study demonstrates that 7.7% of women with PT harbor germline P/LP variants in genes associated with AD cancer conditions. Early identification of these variants has implications for screening, risk reduction, and/or treatment. National guidelines for women with PT do not currently address germline genetic testing, which could be considered.

Disease-specific survival outcomes for patients after locoregional treatment for ductal carcinoma in situ: observational cohort study.

BACKGROUND: Breast-conserving surgery alone, breast-conserving surgery with adjuvant radiation treatment, and mastectomy are guideline-concordant treatments for ductal carcinoma in situ. The aim of this study was to compare survival outcomes between these treatment options. METHODS: A stratified random sample of patients diagnosed with pure ductal carcinoma in situ between 2008 and 2014 was selected from 1330 sites in the USA. Data on diagnosis, treatment, and follow-up were abstracted by local cancer registrars. Population-averaged marginal estimates of disease-specific survival and overall survival for breast-conserving surgery alone, breast-conserving surgery with radiation treatment, and mastectomy were obtained by combining sampling and overlap weights. RESULTS: A total of 18 442 women were included, with a median follow-up of 67.8 (interquartile range 46.1-93.5) months. A total of 35 women died from breast cancer, at a median age of 62 (interquartile range 50-74) years. Population-averaged 8-year rates of disease-specific survival were 99.6% or higher for all treatment groups, with no significant differences between groups (breast-conserving surgery alone versus breast-conserving surgery with radiation treatment, HR 1.19 (95% c.i. 0.29 to 4.85); and mastectomy versus breast-conserving surgery with radiation treatment, HR 1.74 (95% c.i. 0.53 to 5.72). There was no difference in overall survival between the patients who underwent a mastectomy and the patients who underwent breast-conserving surgery with radiation treatment (HR 1.09 (95% c.i. 0.83 to 1.43)). Patients who underwent breast-conserving surgery alone had lower overall survival compared with the patients who underwent breast-conserving surgery with radiation treatment (HR 1.29 (95% c.i. 1.00 to 1.67)). This survival difference vanished for all but one subgroup, namely patients less than 65 years (HR 1.86 (95% c.i. 1.15 to 3.00)). CONCLUSION: There was no statistically significant difference in disease-specific survival between women operated with breast-conserving surgery alone, breast-conserving surgery with radiation treatment, or mastectomy for ductal carcinoma in situ. Given the low absolute risk of disease-specific mortality, these results provide confidence in offering individualized locoregional treatment without fear of compromising survival.

Examining inequities associated with incarceration among breast cancer patients.

INTRODUCTION: Breast cancer treatment patterns and quality of care among patients experiencing incarceration are underexplored. This study examined associations between incarceration and breast cancer disease and treatment characteristics. METHODS: This retrospective analysis was conducted at a tertiary center in the Southeastern United States that serves as the state's safety-net hospital and primary referral site for the state's prisons. All patients ≥18 years diagnosed with breast cancer between 4/14/2014-12/30/2020 were included. Incarceration status was determined through electronic health record review. Linear regression was used to estimate the association of incarceration with time to treatment. Unadjusted overall survival (OS) was estimated using the Kaplan-Meier method with log-rank tests to compare groups. RESULTS: Of the 4329 patients included, 30 (0.7%) were incarcerated at the time of diagnosis or treatment (DI) and 4299 (99.3%) had no incarceration history (NI). Compared to patients who were NI, patients who were DI were younger (p < 0.001), more likely to be unmarried (p < 0.001), and more likely to have family history of breast cancer (p = 0.02). Patients who were DI had an increased time from diagnosis to neoadjuvant chemotherapy (+47.2 days on average, 95% CI 3.9-90.5, p = 0.03) and from diagnosis to surgery (+20 days on average, 95% CI 6.5-33.5, p = 0.02) compared to NI patients. No difference in OS was observed (log-rank p = 0.70). CONCLUSIONS: Patients who are incarcerated experienced significant delays in breast cancer care. While no differences in mortality were appreciated, these findings are concerning, as they indicate poorer care coordination for patients who are incarcerated. Further research is necessary to understand the full scope of these disparities and elucidate factors that contribute to them.

Comparison of incident breast cancer cases in the largest national US tumor registries.

BACKGROUND: This study compared incident breast cancer cases in the National Cancer Database (NCDB) and Surveillance, Epidemiology, End Results Program (SEER) to a national population cancer registry. METHODS: Patients with malignant or in situ breast cancer (BC) 2010-2019 in the NCDB and SEER were compared to the US Cancer Statistics (USCS). Case coverage was estimated as the number of patients in the NCDB/SEER as a proportion of USCS cases. RESULTS: The USCS reported 3,047,509 patients; 77.5% patients were included in the NCDB and 46.0% in SEER. Case ascertainment varied significantly by patient sex (both registries, p < .001). For males, 84.1% were captured in the NCDB, whereas only 77.5% of females were included. Case coverage in SEER was better for females than males (46.1% vs. 43.5%). Registries varied significantly by race/ethnicity (both p < .001). Case coverage in the NCDB was highest for non-Hispanic White (78.2%), non-Hispanic Black (77.7%), and non-Hispanic Asian or Pacific Islander (72.5%) BC patients, and lowest for Hispanic (56.4%) and non-Hispanic American Indian/Alaska Native (41.1%) patients. In SEER, case coverage was highest for non-Hispanic Asian or Pacific Islander (78.1%) and Hispanic (69.6%) patients and it was significantly lower for all other subgroups (non-Hispanic Black, 44.8%; non-Hispanic White, 42.4%; and non-Hispanic American Indian/Alaska Native, 36.6%). CONCLUSIONS: National US tumor registries provide data for a large sampling of breast cancer patients, yet significant differences in case coverage were observed based on age, sex, and race/ethnicity. These findings suggest that analyses using these data sets and interpretation of findings should account for these meaningful variances.

Assessment of Treatment Sequence in Patients With Stage III Breast Cancer.

INTRODUCTION: Stage III breast cancer is defined as locally advanced breast cancer and is treated with curative intent. Historically, overall survival (OS) did not differ based on treatment sequence (neoadjuvant chemotherapy [NAC] followed by surgery versus surgery followed by chemotherapy). Given recent advancements, we examined if treatment sequence may be associated with improved OS in a contemporary cohort of patients with stage III breast cancer. METHODS: Patients aged 18-80 years with prognostic stage III breast cancer who received chemotherapy and surgery were selected from the Surveillance, Epidemiology, and End Results database. Patients were stratified by treatment sequence (NAC versus surgery first). Unadjusted OS and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and compared with log-rank tests. Cox proportional hazards models were used to estimate the association of treatment sequence with OS and BCSS after adjustment for selected covariates. RESULTS: The study included 26,573 patients; median follow-up was 62.0 months (95% confidence interval [CI] 61.0-63.0). Patients receiving NAC had a worse OS and BCSS compared to those who underwent surgery first (5-year OS rates 0.66 versus 0.73; 5-year BCSS rates 0.70 versus 0.77; both log-rank P < 0.001). After adjustment for tumor subtype, receipt of NAC (versus surgery first) remained associated with a worse OS (hazard ratio 1.27, 95% CI 1.2-1.34, P < 0.001) and BCSS (hazard ratio 1.35, 95% CI 1.27-1.43, P < 0.001). CONCLUSIONS: Based on data from patients treated largely before 2020, undergoing surgery first may be associated with improved survival, even after adjustment for known covariates including tumor subtype. These findings may inform treatment when caring for patients with operable, locally advanced breast cancer.

Rates of Pathologic Complete Response and Overall Survival in Patients with Inflammatory Breast Cancer: A National Cancer Database Study.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have worse survival compared with stage III non-IBC matched cohorts; however, the prognostic significance of achieving pathologic complete response (pCR) in the setting of IBC is not well described. We evaluated overall survival (OS) between IBC patients and non-IBC patients who achieved pCR. METHODS: Adult females diagnosed in 2010-2018 with clinical prognostic stage III unilateral invasive breast cancer treated with neoadjuvant chemotherapy (NAC) followed by surgery were selected from the National Cancer Database. Unadjusted OS from surgery was estimated using the Kaplan-Meier method, and log-rank tests were used to compare groups. Cox proportional hazard models were used to estimate the association of study groups with OS after adjustment for available covariates. RESULTS: The study included 38,390 patients; n = 4600 (12.0%) IBC and n = 33,790 (88.0%) non-IBC. Overall pCR rates were lower for IBC compared with non-IBC (20.7% vs. 23.3%; p < 0.001). Among those achieving pCR, 5-year mortality was higher for IBC patients (16.4%, 95% confidence interval [CI] 13.9-19.1%) versus non-IBC patients (9.1%, 95% CI 8.4-9.8%; log-rank p < 0.001). Among all patients achieving pCR, IBC remained associated with worse OS compared with non-IBC (hazard ratio 1.48, 95% CI 1.19-1.85; p < 0.001). CONCLUSION: We found a lower pCR rate and worse OS in IBC patients compared with non-IBC stage III patients. Despite effective systemic therapies, achieving a pCR for IBC patients may not carry the same prognostic impact compared with non-IBC stage III patients.

Spatial heterogeneity in sediment phosphorus pools and phosphatase activity in a eutrophic reservoir.

Agriculture is necessary for food production, but agricultural inputs of phosphorus (P) to waterways can lead to harmful algal blooms in downstream reservoirs. Some of the P that enters these water bodies can be stored in reservoir sediments and later contribute to internal P loading, supplementing external P loads carried in from rivers. Increased P can lead to harmful algal blooms. However, how P is cycling in the sediment of these water bodies varies spatially and temporally has been relatively unstudied. Our objective was to understand how P concentration and form vary spatiotemporally, as well as how P is processed in the sediment of the reservoir. We sampled 30 locations in both August and October 2018 around Milford Reservoir (Kansas), a man-made eutrophic reservoir with frequent harmful algal blooms. We collected water chemistry samples, field measurements of temperature, dissolved oxygen, and pH, and sediment samples to analyze for P chemical speciation and phosphatase enzyme activity. We show that P release by phosphatase activity was higher under anaerobic and basic conditions, which subsequently affects spatiotemporal variation in sediment P pools. We found that low oxygen positively influenced phosphatase activity and sediment P pools, and may drive high internal P loading and harmful algal blooms in the summer months. This research increased our understanding of P cycling in a reservoir highly impacted by agricultural inputs and contributed to a small but growing body of research on internal P loading in midwestern reservoirs.

Triple-Negative Breast Cancer in Older Patients: Does SLNB Guide Therapy?

BACKGROUND: Older breast cancer patients represent a heterogeneous population. Studies demonstrate that sentinel lymph node biopsy (SLNB) omission may be appropriate in some clinical scenarios, yet patients with triple-negative breast cancer (TNBC) are often excluded from these studies. This study evaluated differences in treatment and survival for older patients with TNBC based on SLNB receipt and result. METHODS: Patients 70 years old or older with a diagnosis of cT1-2/cN0/M0 TNBC (2010-2019) who underwent surgery were selected from the National Cancer Database. Logistic regression estimated the association of SLNB with therapy, and Cox proportional hazards models estimated the association of SLNB with overall survival (OS) after adjustment for select factors. RESULTS: Of the 15,167 patients included in the study (median age, 77 years), 13.02% did not undergo SLNB, 5.14% had pN1 disease, 0.12% had pN2 disease, and 0.01% had pN3 disease. Most of the patients (83.9%) underwent surgery first, and 16.1% received neoadjuvant chemotherapy. Of those who underwent surgery first and SLNB, 6.2% had pN+ disease. Receipt of SLNB was associated with a higher likelihood of chemotherapy (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.55-2.21), regardless of pN status. Compared with those who did not undergo a SLNB, a negative SLNB was significantly associated with lower mortality (hazard ratio [HR] 0.68; 95% CI 0.63-0.75), although there was no difference for a positive SLNB (HR 1.14; 95% CI 0.98-1.34). The patients receiving chemotherapy first showed no difference in survival based on SLNB receipt or result (p = 0.23). CONCLUSIONS: Most older patients with TNBC do not have nodal involvement and do not receive chemotherapy. The receipt and results of SLNB may be associated with outcomes for some who undergo surgery first, but not for those who receive neoadjuvant chemotherapy.

"Older people will die of old age. I'll die of climate change": engaging children and young people in climate decision making for public health.

BACKGROUND: The climate crisis is a significant risk to the health and wellbeing of children, young people, and future generations. While there are calls for children and young people's engagement in climate decision making, current power structures limit their participation. This paper aimed to understand children's perspectives about the impact of the climate crisis on their futures, their ability to influence climate decisions, and strategies and mechanisms to facilitate their greater engagement in decisions made about the climate crisis. METHODS: Online in-depth interviews were conducted with n = 28 children (aged 12-16 years) across Australia. Photo elicitation techniques were used to prompt discussion about how the climate crisis impacted their futures, their ability to influence climate decisions, and strategies and mechanisms to engage them in climate decision making. A reflexive approach to thematic analysis was used to construct three themes from data. Images were analysed for ascribed meanings. RESULTS: First, participants stated that they and future generations will inherit the climate crisis from older generations, specifically decision makers. Second, they described a need to address a range of age-related barriers that limit children and young people's engagement in climate decision making, including perceptions about their capabilities. Finally, they discussed strategies and mechanisms to embed children and young people's perspectives within climate decision making, including at civic and political levels. CONCLUSIONS: Children and young people have the right to be involved in decisions made about the climate crisis which significantly impact their futures, including their health and wellbeing. They argue for structural changes to embed their views in climate decision making, and describe a range of engagement strategies and mechanisms to structure their perspectives and knowledge with decision making processes. Furthermore, genuine involvement of children and young people in climate discussions must avoid youthwashing and tokenistic participation. The public health community can help address barriers to youth participation in climate action and should actively engage and collaborate with children and young people to facilitate their political and democratic influence over the climate crisis. This involves making room and creating an accessible seat at the decision making table to ensure their perspectives are embedded in climate decisions.

Trajectory of Subsequent Breast Cancer Diagnoses in a Diverse Patient Cohort with Breast Atypia.

BACKGROUND: Proliferative breast atypical lesions, including atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasms (LIN), represent benign entities that confer an elevated risk of ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC). However, the timing of disease progression is variable and risk factors associated with the trajectory of disease are unknown. METHODS: Patients diagnosed with ADH or LIN from 1992 to 2017 at an academic center were identified. Early progression was defined as DCIS or IBC diagnosed within 5 years following the initial atypia diagnosis. Unadjusted cancer-free survival was estimated using the Kaplan-Meier method. Demographics, clinicopathologic features, and use of chemoprevention were compared between the early and late development groups. RESULTS: Overall, 418 patients were included-73.7% with ADH and 26.3% with LIN. Over a median follow up of 92.1 months, 71/418 (17.0%) patients developed IBC (57.7%) or DCIS (42.3%). Almost half (47.9%, 34/71) were diagnosed within 5 years of their initial atypia diagnosis, and 52.1% (37/71) were diagnosed after 5 years. Patient and atypia characteristics were not associated with rate of events or time to events. There was a trend of early events being more often ipsilateral (76.5% early vs. 54.1% late; p = 0.13) versus contralateral. CONCLUSIONS: In a large cohort of patients with breast atypia and long-term follow up, 17% experienced subsequent breast events, with approximately half of the events occurring within the first 5 years following the initial atypia diagnosis. Clinical features were not associated with the trajectory to subsequent events, supporting that atypia signals both local and overall malignancy risk.

Demographics and Clinical Decision Making in Patients with Germline Moderate Penetrance Non-BRCA Mutations in Breast Cancer Related Genes.

BACKGROUND: Management of pathogenic variants in high penetrance genes related to breast cancer (BC), such as BRCA1 and BRCA2, are well established. However, moderate penetrance mutations are understudied. We aim to compare risk reduction decision-making patterns in patients with a moderate penetrance BC-related genetic mutations, without a prior BC diagnosis. PATIENTS AND METHODS: Female patients aged ≥ 18 years who tested positive for a BRCA1/2, high penetrance, or moderate penetrance mutation related to BC between 1996 and 2023 without a concurrent or prior BC diagnosis were retrospectively identified from a single academic center's database. Groups were stratified by mutation type: BRCA1/2 mutations (BRCA1, BRCA2), high penetrance mutations (HPM; CDH1, PALB2, PTEN, STK11, TP53), or moderate penetrance mutations (MPM; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D). Demographics and clinical outcomes were compared. RESULTS: A total of 528 patients met the inclusion criteria, with 66% (n = 350) having a BRCA1/2 mutation, 8% (n = 44) having HPM, and 25% (n = 134) having MPM; the median follow-up was 56.0 months. In our cohort, 20.9% of patients with BRCA mutations, 9.1% with HPM, and 7.5% with MPM chose to undergo risk-reducing mastectomies (RRM). Within the moderate penetrance cohort, patients who chose to undergo RRM were younger at the time of genetic testing (39.4 vs. 47.5 years, p = 0.03) and had a higher number of family members with BC (2 vs. 1, p = 0.05). CONCLUSIONS: Our findings provide insights into the demographic characteristics and family history of patients with moderate penetrance mutations and those who pursue risk-reducing surgery.

Utility of Axillary Staging in Older Patients with HER2-Positive Breast Cancer.

BACKGROUND: The utility of sentinel lymph node biopsy (SLNB) in older patients remains controversial. Advancements in human epidermal growth factor receptor 2 (HER2)-directed therapy have revolutionized disease response rates and prognosis, supporting efforts to re-evaluate the utility of SLNB. We aimed to assess the differences in treatment and overall survival (OS) in older patients with HER2-positive breast cancer based on SLNB. METHODS: Using the National Cancer Database (2010-2020), patients ≥ 70 years of age diagnosed with cT1-2/cN0/M0, HER2-positive breast cancer were identified. Logistic regression assessed associations with SLNB, systemic therapy, and radiation. Cox proportional hazard models were used to identify factors associated with OS. Analyses were stratified by treatment sequence, i.e. upfront surgery or neoadjuvant therapy (NAT) followed by surgery. RESULTS: Of the 17,609 patients included, 94% underwent upfront surgery (n = 16,492) and the remaining underwent NAT (n = 1117). Those who underwent SLNB were more likely to receive adjuvant therapy, irrespective of nodal status {upfront surgery/systemic therapy (odds ratio [OR] 2.82, 95% confidence interval [CI] 2.17-3.67); upfront surgery/radiation (OR 3.97, 95% CI 3.03-5.21); NAT/radiation (OR 5.69, 95% CI 1.83-17.69)}. The breast pathologic complete response (pCR) rate was highest among the hormone receptor (HR)-negative/HER2-positive subtype (50.0%), of which none were found to be ypN+. Comorbidity burden was associated with significantly lower rates of adjuvant systemic therapy and worse OS. CONCLUSIONS: Patients who underwent SLNB, regardless of pN status, were more likely to receive adjuvant therapy. Nodal positivity is exceedingly rare for patients with a breast pCR following NAT, especially among the HR-negative/HER2-positive subtype. It is reasonable to consider omission of SLNB in select subgroups of older patients with HER2-positive breast cancer.