Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2- breast tumor cells.

The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor-positive, human epidermal growth factor 2 receptor-negative (ER+/HER2-) breast tumor cells. Despite the drug's success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib-a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle "paths" that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.

Role of minimally invasive surgery in the management of localized pancreatic ductal adenocarcinoma: a review.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with a minority of patients eligible for curative-intent surgical intervention. Pancreatic resections are technically demanding operations associated with considerable morbidity and mortality. Minimally invasive pancreatic resections (MIPRs), which include laparoscopic and robotic approaches, may enhance postoperative outcomes by lessening physiological impact of open surgery. A limited number of randomized-controlled trials as well as numerous retrospective reports have focused on MIPR outcomes and role in management of a variety of tumors, including PDAC. Today, MIPRs are generally considered acceptable alternatives to open surgery as a trend towards improved short-term metrics is observed. However, several questions remain regarding the oncological adequacy of MIPR's as long-term experience is less extensive compared to open techniques. This review aims to summarize existing evidence on MIPRs with a focus on PDAC.

Genetic Ancestry-specific Molecular and Survival Differences in Admixed Patients With Breast Cancer.

OBJECTIVE: We aim to determine whether incremental changes in genetic ancestry percentages influence molecular and clinical outcome characteristics of breast cancer in an admixed population. BACKGROUND: Patients with breast cancer are predominantly characterized as "Black" or "White" based on self-identified race/ethnicity or arbitrary genetic ancestry cutoffs. This limits scientific discovery in populations that are admixed or of mixed race/ethnicity as they cannot be classified based on historical race/ethnicity boxes or genetic ancestry cutoffs. METHODS: We used The Cancer Genome Atlas cohort and focused on genetically admixed patients that had less than 90% European, African, Asian, or Native American ancestry. RESULTS: Genetically admixed patients with breast cancer exhibited improved 10-year overall survival relative to those with >90% European ancestry. Within the luminal A subtype, patients with lower African ancestry had longer 10-year overall survival compared to those with higher African ancestry. The correlation of genetic ancestry with gene expression and DNA methylation in the admixed cohort revealed novel ancestry-specific intrinsic PAM50 subtype patterns. In luminal A tumors, genetic ancestry was correlated with both the expression and methylation of signaling genes, while in basal-like tumors, genetic ancestry was correlated with stemness genes. In addition, we took a machine-learning approach to estimate genetic ancestry from gene expression or DNA methylation and were able to accurately calculate ancestry values from a reduced set of 10 genes or 50 methylation sites that were specific for each molecular subtype. CONCLUSIONS: Our results suggest that incremental changes in genetic ancestry percentages result in ancestry-specific molecular differences even between well-established PAM50 subtypes which may influence disparities in breast cancer survival outcomes. Accounting for incremental changes in ancestry will be important in future research, prognostication, and risk stratification, particularly in ancestrally diverse populations.

Single-Cell Transcriptional and Epigenetic Profiles of Male Breast Cancer Nominate Salient Cancer-Specific Enhancers.

Male breast cancer represents about 1% of all breast cancer diagnoses and, although there are some similarities between male and female breast cancer, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies. To date, most male breast cancers (MBCs) are treated according to protocols established for female breast cancer (FBC). Thus, defining the transcriptional and epigenetic landscape of MBC with improved resolution is critical for developing better avenues for therapeutic intervention. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles at single-cell resolution of two treatment naïve MBC tumors processed immediately after surgical resection. These data enable the detection of differentially expressed genes between male and female breast tumors across immune, stromal, and malignant cell types, to highlight several genes that may have therapeutic implications. Notably, MYC target genes and mTORC1 signaling genes were significantly upregulated in the malignant cells of MBC compared to the female counterparts. To understand how the regulatory landscape of MBC gives rise to these male-specific gene expression patterns, we leveraged the scATAC-seq data to systematically link changes in chromatin accessibility to changes in gene expression within each cell type. We observed cancer-specific rewiring of several salient enhancers and posit that these enhancers have a higher regulatory load than lineage-specific enhancers. We highlight two examples of previously unannotated cancer-cell-specific enhancers of ANXA2 and PRDX4 gene expression and show evidence for super-enhancer regulation of LAMB3 and CD47 in male breast cancer cells. Overall, this dataset annotates clinically relevant regulatory networks in male breast tumors, providing a useful resource that expands our current understanding of the gene expression programs that underlie the biology of MBC.

Tamoxifen Response at Single-Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors.

PURPOSE: In estrogen receptor-positive (ER+)/HER2- breast cancer, multiple measures of intratumor heterogeneity are associated with a worse response to endocrine therapy. We sought to develop a novel experimental model to measure heterogeneity in response to tamoxifen treatment in primary breast tumors. EXPERIMENTAL DESIGN: To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live normal breast specimens and human tumors immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. Live primary cell suspensions were treated ex vivo with tamoxifen (10 µmol/L) or control media for 12 hours, and single-cell RNA libraries were generated using the 10X Genomics droplet-based kit. RESULTS: In total, we obtained and processed normal breast tissue from two women undergoing reduction mammoplasty and tumor tissue from 10 women with ER+/HER2- invasive breast carcinoma. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from resistant subpopulations predict poor outcomes in two large cohorts of ER+ breast cancer patients and are enriched in endocrine therapy-resistant tumors. CONCLUSIONS: This novel ex vivo model system now provides the foundation to define responsive and resistant subpopulations within heterogeneous human tumors, which can be used to develop precise single cell-based predictors of response to therapy and to identify genes and pathways driving therapeutic resistance.

Omission of Axillary Dissection in Node Positive Breast Cancer After Neoadjuvant Systemic Therapy.

INTRODUCTION: Guidelines recommend axillary lymph node dissection (ALND) for ypN + positive patients as patients receiving neoadjuvant systemic therapy (NST) were excluded from trials omitting ALND in pN + patients. We sought to characterize trends in omission of ALND in patients with ypN + disease. METHODS: Adult women with invasive breast carcinoma in the National Cancer Database between 2012 and 2019 who received NST (chemotherapy or endocrine) and had ypN + disease were included. Patients were excluded if they did not have definitive surgery within eight months of diagnosis. The primary study outcome was completion of ALND versus omission. Differences in demographics, tumor characteristics, and treatment were identified using bivariate and multivariate logistic regression models. RESULTS: In total, 103,121 women were included. Most had cT1 (26%) or cT2 (45%) tumors, cN + disease (71%), and ductal histology (83%). 69% of patients received neoadjuvant chemotherapy and 31% neoadjuvant endocrine without chemotherapy (30% both). ALND was performed in 77% of patients. Omission of ALND became more prevalent each year from 2012 (14%) to 2019 (34%). On multivariate modeling, year of diagnosis, black race, cN status, higher grade, estrogen receptor+/HER2-receptor subtype, and mastectomy were associated with increased prevalence of ALND. Age, Charlson/Deyo comorbidity index score, endocrine versus chemotherapy, and adjuvant radiation were not associated with receipt of ALND. CONCLUSIONS: Despite guidelines recommending ALND, omission is common in patients with ypN + breast cancer after NST. Omission of ALND increased significantly over time and is associated with clinical and demographic factors. Future study is needed to determine the oncologic safety of this approach.

Advances in the Management of Early-Stage Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with both inter- and intratumor heterogeneity, thought to result in a more aggressive course and worse outcomes. Neoadjuvant therapy (NAT) has become the preferred treatment modality of early-stage TNBC as it allows for the downstaging of tumors in the breast and axilla, monitoring early treatment response, and most importantly, provides important prognostic information that is essential to determining post-surgical therapies to improve outcomes. It focuses on combinations of systemic drugs to optimize pathologic complete response (pCR). Excellent response to NAT has allowed surgical de-escalation in ideal candidates. Further, treatment algorithms guide the systemic management of patients based on their pCR status following surgery. The expanding knowledge of molecular pathways, genomic sequencing, and the immunological profile of TNBC has led to the use of immune checkpoint inhibitors and targeted agents, including PARP inhibitors, further revolutionizing the therapeutic landscape of this clinical entity. However, subgroups most likely to benefit from these novel approaches in TNBC remain elusive and are being extensively studied. In this review, we describe current practices and promising therapeutic options on the horizon for TNBC, surgical advances, and future trends in molecular determinants of response to therapy in early-stage TNBC.

High expression of the RET receptor tyrosine kinase and its ligand GDNF identifies a high-risk subset of estrogen receptor positive breast cancer.

PURPOSE: Resistance to endocrine therapy is the primary cause of treatment failure and death in patients with ER-positive (ER +)/luminal breast cancer. Expression and activation of the RET receptor tyrosine kinase may be driving poor outcomes. We aim to identify high-risk patients and druggable pathways for biomarker-based clinical trials. METHODS: We obtained batch-normalized mRNA expression data from Breast Invasive Carcinoma-The Cancer Genome Atlas, PanCancer Atlas (BRCA-TCGA). To determine clinically significant cutoffs for RET expression, patients were grouped at different thresholds for Kaplan-Meier plotting. Differential gene expression (DGE) analysis and enrichment for gene sets was performed. transcriptomic dataset of antiestrogen-treated ER + tumors stratified by clinical response was then analyzed. RESULTS: High RET expression was associated with worse outcomes in patients with ER + tumors, and stratification was enhanced by incorporating GDNF expression. High RET/GDNF patients had significantly lower overall survival (HR = 2.04, p = 0.012), progression-free survival (HR = 2.87, p < 0.001), disease-free survival (HR = 2.67, p < 0.001), and disease-specific survival (HR = 3.53, p < 0.001) than all other ER + patients. High RET/GDNF tumors were enriched for estrogen-independent signaling and targetable pathways including NTRK, PI3K, and KRAS. Tumors with adaptive resistance to endocrine therapy were enriched for gene expression signatures of high RET/GDNF primary tumors. CONCLUSION: Expression and activation of the RET receptor tyrosine kinase may be driving poor outcomes in some patients with ER + breast cancer. ER + patients above the 75th percentile may benefit from clinical trials with tyrosine kinase inhibitors.

Tamoxifen Response at Single Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors.

In ER+/HER2- breast cancer, multiple measures of intra-tumor heterogeneity are associated with worse response to endocrine therapy. To investigate heterogeneity in response to treatment, we developed an operating room-to-laboratory pipeline for the collection of live human tumors and normal breast specimens immediately after surgical resection for processing into single-cell workflows for experimentation and genomic analyses. We demonstrate differences in tamoxifen response by cell type and identify distinctly responsive and resistant subpopulations within the malignant cell compartment of human tumors. Tamoxifen resistance signatures from 3 distinct resistant subpopulations are prognostic in large cohorts of ER+ breast cancer patients and enriched in endocrine therapy resistant tumors. This novel ex vivo model system now provides a foundation to define responsive and resistant sub-populations within heterogeneous tumors, to develop precise single cell-based predictors of response to therapy, and to identify genes and pathways driving resistance to therapy.

A Review of Immune Checkpoint Blockade for the General Surgeon.

The immune system is a complex and interconnected system that has evolved to protect its host from foreign pathogens. CD8+ T cells are a type of immune cell that can be directly lethal to tumor cells. However, their tumor killing capabilities can be inhibited by checkpoint molecules. During the last decade, the development of medications that block these checkpoint molecules has revolutionized treatment for some cancer types and indications for use continue to grow. As usage of immunotherapy increases, toxicities and adverse events unique to immunotherapy are becoming more prevalent. Here, we review the commonly targeted inhibitory molecules along with their food and drug administration-approved indications in various cancer therapeutic regimens, immunotherapy-related toxicities, and how this may impact surgical planning.

Tumor Grade Predicts for Calcitonin Doubling Times and Disease-Specific Outcomes After Resection of Medullary Thyroid Carcinoma.

Background: Tumor grade is a new validated prognostic factor for medullary thyroid cancer (MTC). Calcitonin doubling time can predict MTC recurrence. We aimed to describe the association of tumor grade with calcitonin doubling and its effect on disease-specific outcomes times after resection. Methods: A retrospective analysis of MTC patients who underwent resection at a single tertiary-care cancer center between 1986 and 2017 were evaluated. Tumors were designated as high-grade MTC if two head and neck pathologists identified mitotic index ≥5 per 2 mm2, tumor necrosis, or a Ki67 proliferative index ≥5% within the tumor. Calcitonin doubling time was calculated using a validated calculator with at least three consecutive levels. Using Cox proportional hazards models, outcomes evaluated included locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: Among 117 patients, 95 were low grade and 22 high grade. Median follow-up was 70.2 months. High-grade patients demonstrated significantly faster calcitonin doubling times when compared with low-grade patients (8.51 ± 3.22 months vs. 38.42 ± 11.19 months; p < 0.001). In addition, most high-grade patients (66.7%) had calcitonin doubling times less than 1 year compared with fewer low-grade patients (1.0%; p < 0.001). High- and low-grade patients were further stratified by those who had calcitonin doubling times less than or greater than 2 years-a previously validated prognostic cutoff point. For patients with calcitonin doubling times less than 2 years, 70% were high grade, while 30% were low grade (p < 0.001). On multivariate analysis comparing grade and calcitonin doubling times, high-grade patients had significantly worse LRFS (hazards ratio [HR] 4.77 [confidence interval; CI 1.19-8.81]), DMFS (HR 7.25 [CI 2.36-22.28]), and OS (HR 6.04 [CI 1.85-19.72]; p < 0.05 for all), while calcitonin doubling times less than 2 years had worse DMFS (HR 7.22 [CI 1.05-49.75]). High-grade patients with calcitonin doubling times less than 2 years had associated worse LRFS and OS (both p < 0.05) compared with low-grade patients. Conclusions: The majority of high-grade MTC patients have calcitonin doubling times less than 2years. Close monitoring should be advocated for patients assessed to have high-grade tumors as they are at risk for poor disease-specific outcomes and structural recurrence.

Prevalence of Pathologic N2/N3 Disease in Postmenopausal Women with Clinical N0 ER+/HER2- Breast Cancer.

BACKGROUND: The RxPONDER trial demonstrated that the 21-gene recurrence score can be used to guide adjuvant systemic therapy decisions in postmenopausal women with pN1 ER+/HER2- breast cancer. As such, a sentinel lymph node biopsy (SLNB) may not provide systemic treatment-altering information for many patients, and omission of SLNB in patients with low probability of pN2/N3 disease could be considered. METHODS: Postmenopausal women (aged ≥ 50 years) diagnosed with cN0cM0, ER+/HER- breast cancer from 2013 to 2017 were identified in the National Cancer Database. The primary outcome was the prevalence of pN2/N3 disease. RESULTS: Of 325,692 postmenopausal women with cN0 ER+/HER2- breast cancer, 7106 (2.2%) were pN2/N3. In total, 81.7% had cT1 tumors, 16.8% T2, 1.3% T3, and 0.2% T4. In patients with T1 tumors, the prevalence of pN2/N3 disease was 1.2% compared with 17.2% in patients with T3/T4 tumors. In multivariable models, cT stage was the strongest predictor of pN2/N3 disease (adjusted odds ratio [aOR] 14.9 [12.1-18.4]). Lobular histology (aOR 2.4 [2.3-2.6]), higher grade (aOR 2.9 [2.6-3.1]), and young age (aOR 1.5 [1.3-1.7]) were also associated with increased prevalence of pN2/N3. We created a model using histology, grade, and T stage that stratifies patients with low prevalence of pN2/3 disease (< 1%) and those at high risk (> 20%). CONCLUSIONS: In postmenopausal women with cN0 ER+/HER2- breast cancer, the prevalence of pN2/N3 disease is low, indicating a potential opportunity to use the results of RxPONDER to extend criteria to omit SLNB. Prospective study is needed to determine safety, including risk of nodal recurrence, of omission of SLNB in carefully selected patients.

Pathologic complete response and survival after neoadjuvant chemotherapy in cT1-T2/N0 HER2+ breast cancer.

Women with small HER2+ breast cancers may have excellent prognosis with adjuvant single-agent chemotherapy and HER2-targeted therapy. The role of de-escalated therapy in the neoadjuvant setting, however, remains uncertain. We conducted a cohort study of adult women with T1-2/cN0 HER2+ breast cancer diagnosed 2013-2016 in the National Cancer Database treated with neoadjuvant chemotherapy (NAC) and HER2-targeted therapy. Factors associated with pathologic complete response (pCR) and overall survival were examined. In total, 6994 patients were included, 32% cT1 and 68% cT2. Multi-agent NAC was given to 90% of women while single-agent NAC was given to 10% of women. pCR was achieved in 46% of cT2 patients and 43% of cT1, and in 46% of patients treated with multi-agent versus 38% single agent. Patients receiving multi-agent chemotherapy were younger, had fewer comorbidities, and had higher cT stage and grade. In all patients, pCR was associated with improved survival (p < 0.01). Multi-agent chemotherapy (OR 1.3, p = 0.003), hormone receptor negative (OR 2.6, p < 0.001), higher grade (OR 2.2, p < 0.001), younger age (OR 1.4, p = 0.011), and later year of diagnosis (OR 1.3, p = 0.005) were associated with achieving pCR. Multi-agent chemotherapy was associated with higher likelihood of pCR, but this effect was modest compared to other factors. Single-agent NAC with HER2-directed therapy in selected patients may provide excellent outcome with reduced toxicity, while allowing escalated therapy in the adjuvant setting for patients with residual disease. Prospective studies are needed to determine effects of de-escalation in the neoadjuvant setting on survival and optimal selection strategies.

Does Angiosarcoma of the Breast Need Nodal Staging?

BACKGROUND: Breast angiosarcoma is a rare malignancy classically associated with hematogenous metastases. We sought to determine the prevalence of pathologic nodal involvement in patients with nonmetastatic, resected breast angiosarcoma and its association with overall survival. STUDY DESIGN: The National Cancer Database was used to identify patients with nonmetastatic angiosarcoma of the breast who underwent surgical resection from 2004 to 2017. The prevalence of regional lymph node operation and nodal positivity was calculated. The Kaplan-Meier method was used to evaluate overall survival among node-positive and node-negative patients. Cox proportional hazard modeling was used to evaluate the adjusted association of nodal positivity with overall survival. RESULTS: We included 991 patients with angiosarcoma. The median age was 69 years (interquartile range 57 to 78), and the cohort was 99% female. A total of 298 patients (30%) had pathologic regional nodal evaluation. Of those, 15 (5.0%) had positive regional lymph nodes. Node-positive patients had significantly worse survival than patients with negative regional lymph nodes. After adjusting for patient, tumor, and treatment factors, a positive regional lymph node was associated with worse overall survival compared with patients with no nodal evaluation (hazard ratio 3.20; 95% CI 1.75 to 5.86; p < 0.001). CONCLUSIONS: Patients with nonmetastatic angiosarcoma of the breast have a 5% regional lymph node positivity rate, which is at a common threshold to consider evaluation, and identifies patients with poor survival. A prospective study to determine performance characteristics of sentinel lymph node biopsy is warranted.

Sociodemographic and Clinical Predictors of Neoadjuvant Chemotherapy in cT1-T2/N0 HER2-Amplified Breast Cancer.

BACKGROUND: The optimal treatment strategy for small node-negative human epidermal growth factor receptor 2-positive (HER2+) breast cancer remains controversial. Neoadjuvant chemotherapy may risk overtreatment, whereas surgery first fails to identify patients with residual disease in need of escalated adjuvant systemic therapy. We investigated patient characteristics associated with receipt of neoadjuvant chemotherapy. METHODS: Adult women with cT1-T2/N0, HER2+ breast cancer between 2013 and 2017 in the National Cancer Database who underwent surgery within 8 months of diagnosis were included. Patients were classified as receiving neoadjuvant chemotherapy versus a surgery-first approach. We assessed the sociodemographic and clinical predictors of neoadjuvant chemotherapy versus surgery first and associations between neoadjuvant chemotherapy and breast cancer treatments using multivariable regression models. RESULTS: We identified 56,784 women, of whom 12,758 (22%) received neoadjuvant chemotherapy, 29,139 (53%) received adjuvant chemotherapy, 12,907 (24%) received no chemotherapy, and 1980 were missing chemotherapy information. After adjustment, cT2 stage was the strongest predictor of neoadjuvant chemotherapy compared with surgery first. Younger age and later diagnosis year were positively associated with receipt of neoadjuvant chemotherapy. In contrast, hormone receptor positivity, Black race, rural county, and government-funded or no health insurance were inversely associated with neoadjuvant chemotherapy. In multivariable analyses, patients who received neoadjuvant chemotherapy were more likely to have a mastectomy (vs. lumpectomy) and sentinel lymph node biopsy or no nodal surgery (vs. axillary lymph node dissection). Patients who received neoadjuvant chemotherapy were more likely to receive multi-agent (vs. single-agent) chemotherapy than those who received adjuvant chemotherapy. CONCLUSIONS: Substantial differences in the utilization of neoadjuvant chemotherapy exist in women with HER2+ breast cancer, which reflect both clinical parameters and disparities. Optimal treatment strategies should be implemented equitably across sociodemographic groups.

International Medullary Thyroid Carcinoma Grading System: A Validated Grading System for Medullary Thyroid Carcinoma.

PURPOSE: Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC. PATIENTS AND METHODS: Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm2, Ki67 proliferative index ≥ 5%, or tumor necrosis. RESULTS: Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio [HR] = 11.490; 95% CI, 3.118 to 32.333; P < .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327; P = .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261; P = .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193; P = .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers. CONCLUSION: This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.

Bridging Endocrine Therapy for HR+/HER2- Resectable Breast Cancer: Is it Safe?

BACKGROUND: The COVID-19 pandemic has required new treatment paradigms to limit exposures and optimize hospital resources, including the use of neoadjuvant endocrine therapy (NAET) as bridging therapy for HR+/HER2-invasive tumors and DCIS. While this approach has been used in locally advanced disease, it is unclear how it may affect outcomes in resectable HR+/HER2- tumors. METHODS: Women ≥18 years diagnosed with in situ (Tis) or non-metastatic HR+/HER2- breast cancer from March-May 2019 and 2020 were included. Fisher's exact test and two-sample t test were used to compare baseline characteristics and surgical outcomes between strata. Sub-analysis was performed between patients who received primary surgery vs a bridging NAET approach. RESULTS: Despite similar clinical characteristics, patients in 2019 were more likely to have a surgery-first approach (75% vs 42%, P-value = .0007), receive surgery sooner (22 vs 29 days, P-value < .001), and within 60 days from diagnosis date (100% vs 85%, P-value = .0301). Neoadjuvant endocrine therapy was a more prevalent approach in 2020 (48% vs 7%, P-value < .0001). Rates of clinical to pathologic up-staging remained consistent across primary surgery vs bridging NAET subgroups (P-value = .9253). DISCUSSION: Pandemic-driven treatment protocols provide a unique opportunity to assess the utility of bridging endocrine therapy for resectable HR+/HER2- tumors. Differences in clinical and pathologic staging were similar across groups and did not appear to be affected by receipt of NAET. Our limited cohort demonstrates this strategic therapeutic avenue can optimize health care utilization and may be a reasonable approach when delaying surgery is preferred.