Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis.

The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell-cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER+/luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.

Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419.

Background: Triple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease. Methods: Whole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC-Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed. Results: Primary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM. Conclusions: BrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.

Clinical subtype, treatment response, and survival in De Novo and recurrent metastatic breast cancer.

PURPOSE: This study evaluated whether patients with de novo metastatic breast cancer (MBC) have superior outcomes compared to those with recurrent MBC in a contemporary treatment era and examined factors related to outcome differentials. METHODS: Using an institutional database, we examined patient and tumor characteristics, treatment response, and outcome among 232 patients with de novo and 612 patients with recurrent MBC diagnosed between 2011 and 2017. RESULTS: De novo MBC had 9-month (m) longer overall survival (OS) than recurrent MBC (36.4 vs 27.4 m, p < 0.001). Contributions to this difference included nearly twofold more HER2-positive (29.3% vs 15.2%) and significantly fewer triple-negative breast cancers (20.3% vs 32.4%, both p < 0.001) in de novo compared with recurrent MBC cohorts. Stratified by clinical subtype, progression-free survival (PFS) on first-line therapy was significantly longer in de novo MBC in all but the triple-negative subtype, 25.5 vs 11.6 m (p < 0.001) among 390 patients with hormone receptor-positive, HER2-negative, 11.4 vs 5.4 m (p = 0.002) among 142 patients with HER2-positive, and 4.0 vs 3.0 m (p = 0.121) among 162 with triple-negative MBC. In multivariable analysis, de novo status remained independently associated with improved OS (hazard ratio 0.63, 95% CI 0.49-0.80), regardless of subtype and other features. CONCLUSION: Patients with de novo MBC have better outcomes than those with recurrent MBC. Differences in clinical subtype and response to therapy in the metastatic setting contribute to, but do not fully explain, this difference. Longer PFS to first-line therapy in de novo MBC suggests biologic differences compared to recurrent MBC, which may be intrinsic or due to acquired resistance from treatment for prior localized breast cancer in recurrent disease.

Obesity, comorbidities, and treatment selection in Black and White women with early breast cancer.

BACKGROUND: This study investigates obesity and comorbidity in Black and White women with early breast cancer (stages I-III) and their potential impact on treatment decisions for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) tumors. METHODS: In this retrospective chart review, comparisons of frequencies for Black and White patients were calculated with the Fisher exact test. Log binomial regression was used to estimate prevalence ratios (PRs) with 95% confidence intervals for total and individual comorbidities, and multivariable modeling was used to estimate PRs adjusted for age and body mass index (BMI). RESULTS: In a sample of 548 patients, 26% were Black, and 74% were White. Sixty-two percent of Black patients and 32% of White patients were obese (BMI ≥ 30 kg/m2 ; P < .0001). Seventy-five percent of Black patients and 87% of White patients had HR+ tumors (P = .001). Significant intergroup differences were seen for 2 or more total comorbidities (62% of Blacks vs 47% of Whites; P = .001), 2 or more obesity-related comorbidities (33% vs 10%; P < .0001), hypertension (60% vs 32%; P < .0001), diabetes mellitus (23% vs 6%; P < .0001), hypercholesterolemia or hyperlipidemia (28% vs 18%; P = .02), and hypothyroidism (4% vs 11%; P = .012). In women with HR+/HER2- tumors, there were no intergroup differences in treatment decisions regarding the type of surgery, chemotherapy regimen, radiation, or endocrine treatment despite significant differences in the prevalence of obesity and comorbidities. CONCLUSIONS: This study documents significant disparities between Black and White women with early breast cancer with regard to high rates of obesity, overall comorbidities, and obesity-related comorbidities, and it highlights the prevalence of competing risks that may complicate outcomes in breast cancer.

Weight trajectories in women receiving systemic adjuvant therapy for breast cancer.

BACKGROUND: Weight gain after breast cancer (BC) diagnosis is a well-known phenomenon; however, it is not a universal phenomenon and identification of patients at highest risk for weight gain is needed. This study investigates weight trajectories in early BC patients at 2 years post-primary treatment, examining potential contributing factors such as age, race, and receipt of chemotherapy, anti-HER-2 therapy, and endocrine treatment (ET). METHODS: A single institution cohort of newly diagnosed women age 21 and older with early breast cancer patients (Stage 0-3) were identified by retrospective chart review (diagnosis year 1995 to 2016). Log-binomial regression models for net weight changes at 2 years post-primary treatment including patient demographic, clinical, and treatment characteristics. RESULTS: The final sample of 625 patients included 29% who were non-White and 37% who were pre-menopausal at diagnosis. Body mass index (BMI) at diagnosis was calculated and found to be normal in 33% (BMI 18 to < 25), overweight in 27% (BMI 25 to < 30), and obese in 40% (BMI 30 and higher). At 2 years, compared to weight at diagnosis, 31% had lost > 2 kg, 34% had stable weight ± 2 kg, and 35% had gained > 2 kg. Factors associated with > 2 kg weight gain were menopausal status (pre-menopausal HR 1.65, 95% CI 1.34-2.04, p < .0001), receiving any chemotherapy (HR 1.36, 95% CI 1.04-1.77), and anthracycline-based chemotherapy followed by ET (HR 1.60, CI 1.01-2.45). Anti-HER-2 therapy and transition from pre- to post-menopausal during the 2-year study period were not significant factors in weight gain. In multivariate analysis, menopausal status remained the only significant variable related to weight gain when adjusted for treatment. For all treatment combinations, pre-menopausal women had significantly more weight gain. CONCLUSIONS AND RELEVANCE: Weight gain, weight loss, and stable weight in women with early breast cancer vary greatly by treatment plan. However, pre-menopausal patients have the highest risk for weight gain.

Weight gain in hormone receptor-positive (HR+) early-stage breast cancer: is it menopausal status or something else?

PURPOSE: This study investigates weight trajectories in pre- versus postmenopausal breast cancer (BC) survivors diagnosed with hormone receptor-positive tumors, with a specific focus on discerning menopausal status and type of endocrine treatment (ET) as risk factors for weight gain during ET. METHODS: We conducted a retrospective review of electronic medical records. Descriptive statistics and Chi-squared and t tests were used to compare pre- and postmenopausal women. Chi-squared tests and ANOVA were used for within-group associations between patient characteristics and weight trajectories. Log-binomial regression models were used to estimate relative risk for weight gain. RESULTS: The final sample was 32% premenopausal (n = 140) and 68% postmenopausal (n = 298). Relative risk (RR) for weight gain during ET was highest in women who were premenopausal (RR = 1.29, 1.03-1.52) and had Stage 3 BC (RR = 2.12, 1.59-2.82), mastectomy (RR = 1.49, 1.19-1.88), axillary node dissection (RR = 1.39, 1.11-1.73), and chemotherapy (RR = 1.80, 1.37-2.36). For each kg of weight gained between BC diagnosis and start of ET, and for each additional year of age, RR of gaining weight during ET decreased (RR = 0.98, 0.97-0.99, and RR = 0.99, 0.98-0.99, respectively). Menopausal status and type of ET were not significant predictors of weight gain. In multivariable analysis, only weight loss between BC diagnosis and start of ET was significant. CONCLUSION: The association of weight loss prior to ET and subsequent substantial weight gain during ET warrants further investigation.

Weight changes in postmenopausal breast cancer survivors over 2 years of endocrine therapy: a retrospective chart review.

PURPOSE: Obesity and weight gain after breast cancer (BC) diagnosis can affect cancer outcomes. This study explores the question of weight change during the first 2 years of endocrine treatment (ET) to identify the independent effects of BC diagnosis and treatment on post-diagnosis weight trajectories in early-stage postmenopausal BC survivors. METHODS: The study design is a retrospective chart review. Chi square tests and ANOVA were used to compare patients who gained >2 kg, lost >2 kg, or had stable weight. Log-binomial regression models were used to evaluate associations between patient characteristics and weight trajectories. RESULTS: The final sample is N = 300, with mean age at BC diagnosis of 65 years and 76% white. After 2 years of ET, 39% of study participants had gained >2 kg, 27% had lost >2 kg, and 34% had stable weight. Relative risks (RR) for weight gain were as follows: age at diagnosis = 0.98 (0.96, 0.99), being married = 1.48 (1.04, 2.12), weight change between BC diagnosis and start of ET = 0.98 (0.97, 0.99), Stage II = 1.42 (1.01, 2.01) or Stage III = 1.99 (1.41, 2.82), PR negative = 0.70 (0.51, 0.96), HER2 positive = 1.51 (1.07, 2.13), mastectomy = 1.49 (1.12, 1.98), axillary node dissection = 1.67 (1.27, 2.20), adjuvant chemotherapy = 1.49 (1.02, 2.19), and neoadjuvant chemotherapy = 2.29 (1.67, 3.14). Type of ET (tamoxifen or aromatase inhibitor) was not significant. CONCLUSIONS: In our sample of postmenopausal early-stage BC survivors, a majority had stable or lost weight during the first 2 years of ET. Higher disease complexity and associated treatment posed higher RR for weight gain.

A Multidisciplinary Breast Cancer Brain Metastases Clinic: The University of North Carolina Experience.

BACKGROUND: Breast cancer brain metastasis (BCBM) confers a poor prognosis and is unusual in requiring multidisciplinary care in the metastatic setting. The University of North Carolina at Chapel Hill (UNC-CH) has created a BCBM clinic to provide medical and radiation oncology, neurosurgical, and supportive services to this complex patient population. We describe organization and design of the clinic as well as characteristics, treatments, and outcomes of the patients seen in its first 3 years. METHODS: Clinical and demographic data were collected from patients in a prospectively maintained database. Descriptive statistics are reported as percentages and means. The Kaplan-Meier method was used to estimate time-to-event outcomes. RESULTS: Sixty-five patients were seen between January 2012 and January 2015. At the time of presentation to the BCBM clinic, most patients (74%) had multiple (≥2) brain metastases and had received prior systemic (77%) and whole-brain radiation therapy and/or central nervous system stereotactic radiosurgery (65%) in the metastatic setting. Seventy-eight percent returned for a follow-up visit; 32% were enrolled in a clinical trial. Median time from diagnosis of brain metastasis to death was 2.11 years (95% confidence interval [CI] 1.31-2.47) for all patients, 1.15 years (95% CI 0.4-2.43) for triple-negative breast cancer, 1.31 years (95% CI 0.51-2.52) for hormone receptor-positive/HER2- breast cancer, and 3.03 years (95% CI lower limit 1.94, upper limit not estimable) for HER2+ breast cancer (p = .0037). CONCLUSION: Patients with BCBM have unique and complex needs that require input from several oncologic disciplines. The development of the UNC-CH multidisciplinary BCBM clinic is a model that can be adapted at other centers to provide coordinated care for patients with a challenging and complex disease. IMPLICATIONS FOR PRACTICE: Patients with breast cancer brain metastases often require unique multidisciplinary care to meet the numerous and uncommon challenges associated with their conditions. Here, the development and characteristics of a clinic designed specifically to provide for the multidisciplinary needs of patients with breast cancer brain metastases are described. This clinic may serve as a model for other institutions interested in creating specialty clinics with similar objectives.