Impact of Neoadjuvant Chemoimmunotherapy on Surgical Outcomes and Time to Radiation in Triple-Negative Breast Cancer.

BACKGROUND: We examined the association between immunotherapy-containing and standard chemotherapy regimens with treatment delays and postoperative complications in stage II-III triple-negative breast cancer. The effect of immune-related adverse events (irAEs) was compared. PATIENTS AND METHODS: We compared 139 women treated with neoadjuvant pembrolizumab plus chemotherapy (KEYNOTE-522 regimen) from August 2021 to September 2022 with 287 consecutive patients who received neoadjuvant chemotherapy alone prior to July 2021 and underwent surgery. Baseline characteristics, time to treatments, and surgical complications were compared using two-sample non-parametric tests. Linear regression evaluated association of irAEs with time to surgery and radiation. Logistic regression identified factors associated with surgical complications. RESULTS: Age, body mass index, race, American Society of Anesthesiologists (ASA) class, and mastectomy rates were similar among cohorts. No clinically relevant difference in time from end of neoadjuvant treatment to surgery was observed [KEYNOTE-522: median 32 (IQR 27, 43) days; non-KEYNOTE-522: median 31 (IQR 26, 37) days; P = 0.048]. Time to radiation did not differ (P = 0.7). A total of 26 patients (9%; non-KEYNOTE-522) versus 11 (8%; KEYNOTE-522) experienced postoperative complications (P = 0.6). In the KEYNOTE-522 cohort, 59 (43%) of 137 patients experienced 82 irAEs; 40 (68%) required treatment. Older age (P = 0.018) and ASA class 4 (P = 0.007) were associated with delays to surgery after adjusting for clinical factors. Experiencing ≥ 1 irAE was associated with delay to radiation (P = 0.029). IrAEs were not associated with surgical complications (P = 0.4). CONCLUSIONS: We observed no clinically meaningful difference between times to surgery/adjuvant radiation or postoperative complications and type of preoperative chemotherapy. IrAEs were associated with delay to adjuvant radiation but not with postoperative complications or delay to surgery.

Analysis of Specimen Mammography with Artificial Intelligence to Predict Margin Status.

BACKGROUND: Intraoperative specimen mammography is a valuable tool in breast cancer surgery, providing immediate assessment of margins for a resected tumor. However, the accuracy of specimen mammography in detecting microscopic margin positivity is low. We sought to develop an artificial intelligence model to predict the pathologic margin status of resected breast tumors using specimen mammography. METHODS: A dataset of specimen mammography images matched with pathologic margin status was collected from our institution from 2017 to 2020. The dataset was randomly split into training, validation, and test sets. Specimen mammography models pretrained on radiologic images were developed and compared with models pretrained on nonmedical images. Model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). RESULTS: The dataset included 821 images, and 53% had positive margins. For three out of four model architectures tested, models pretrained on radiologic images outperformed nonmedical models. The highest performing model, InceptionV3, showed sensitivity of 84%, specificity of 42%, and AUROC of 0.71. Model performance was better among patients with invasive cancers, less dense breasts, and non-white race. CONCLUSIONS: This study developed and internally validated artificial intelligence models that predict pathologic margins status for partial mastectomy from specimen mammograms. The models' accuracy compares favorably with published literature on surgeon and radiologist interpretation of specimen mammography. With further development, these models could more precisely guide the extent of resection, potentially improving cosmesis and reducing reoperations.

Outcomes of a pilot virtual mentorship program for medical students interested in surgery.

BACKGROUND: Lack of mentorship may deter medical students who identify as underrepresented minorities (URM) from entering academic surgery. METHODS: 30 mentor-medical student pairs from the AWS 2020 virtual mentorship pilot-program were surveyed pre-and post-program to explore 1) feasibility of meetings, and, 2) program's perceived efficacy in fostering professional development skills. Participants responded using a 5-point Likert scale (1 = not at all; 5 = completely). Proportions of participants in each category were compared. RESULTS: Proportion of participants perceiving monthly meetings to be completely feasible did not differ from pre-to post-program surveys for mentees (75%(21/28) vs. 71%(12/17); p = 0.743) or mentors (71%(17/24) vs 71%(13/18); p = 1.00). Compared to pre-program responses, mentees endorsed "completely" (Likert scale 5) improving with regard to their elevator speech (p = 0.001), developing their curriculum vitae (p = 0.003), ability to network (p = 0.021), and acquiring skills for career advancement (p = 0.003). CONCLUSION: Virtual mentorship may be a feasible and effective means of increasing access to mentors for URM medical students.

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.

The Landscape of Immune Microenvironments in Racially Diverse Breast Cancer Patients.

BACKGROUND: Immunotherapy is a rapidly evolving treatment option in breast cancer; However, the breast cancer immune microenvironment is understudied in Black and younger (<50 years) patients. METHODS: We used histologic and RNA-based immunoprofiling methods to characterize the breast cancer immune landscape in 1,952 tumors from the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1,030) and young women (n = 1,039). We evaluated immune response leveraging markers for 10 immune cell populations, compared profiles to those in The Cancer Genome Atlas (TCGA) Project [n = 1,095 tumors, Black (n = 183), and young women (n = 295)], and evaluated in association with clinical and demographic variables, including recurrence. RESULTS: Consensus clustering identified three immune clusters in CBCS (adaptive-enriched, innate-enriched, or immune-quiet) that varied in frequency by race, age, tumor grade and subtype; however, only two clusters were identified in TCGA, which were predominantly comprised of adaptive-enriched and innate-enriched tumors. In CBCS, the strongest adaptive immune response was observed for basal-like, HER2-positive (HER2+), triple-negative breast cancer (TNBC), and high-grade tumors. Younger patients had higher proportions of adaptive-enriched tumors, particularly among estrogen receptor (ER)-negative (ER-) cases. Black patients had higher frequencies of both adaptive-enriched and innate-enriched tumors. Immune clusters were associated with recurrence among ER- tumors, with adaptive-enriched showing the best and innate-enriched showing the poorest 5-year recurrence-free survival. CONCLUSIONS: These data suggest that immune microenvironments are intricately related to race, age, tumor subtype, and grade. IMPACT: Given higher mortality among Black and young women, more defined immune classification using cell-type-specific panels could help explain higher recurrence and ultimately lead to targetable interventions.

B Cell Function in the Tumor Microenvironment.

The tumor microenvironment (TME) is a heterogeneous, complex organization composed of tumor, stroma, and endothelial cells that is characterized by cross talk between tumor and innate and adaptive immune cells. Over the last decade, it has become increasingly clear that the immune cells in the TME play a critical role in controlling or promoting tumor growth. The function of T lymphocytes in this process has been well characterized. On the other hand, the function of B lymphocytes is less clear, although recent data from our group and others have strongly indicated a critical role for B cells in antitumor immunity. There are, however, a multitude of populations of B cells found within the TME, ranging from naive B cells all the way to terminally differentiated plasma cells and memory B cells. Here, we characterize the role of B cells in the TME in both animal models and patients, with an emphasis on dissecting how B cell heterogeneity contributes to the immune response to cancer.

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.

Healthcare providers' perceived support from their organization is associated with lower burnout and anxiety amid the COVID-19 pandemic.

BACKGROUND: Professional burnout represents a significant threat to the American healthcare system. Organizational and individual factors may increase healthcare providers' susceptibility or resistance to burnout. We hypothesized that during the COVID-19 pandemic, 1) higher levels of perceived organizational support (POS) are associated with lower risk for burnout and anxiety, and 2) anxiety mediates the association between POS and burnout. METHODS: In this longitudinal prospective study, we surveyed healthcare providers employed full-time at a large, multihospital healthcare system monthly over 6 months (April to November 2020). Participants were randomized using a 1:1 allocation stratified by provider type, gender, and academic hospital status to receive one of two versions of the survey instrument formulated with different ordering of the measures to minimize response bias due to context effects. The exposure of interest was POS measured using the validated 8-item Survey of POS (SPOS) scale. Primary outcomes of interest were anxiety and risk for burnout as measured by the validated 10-item Burnout scale from the Professional Quality (Pro-QOL) instrument and 4-item Emotional Distress-Anxiety short form of the Patient Reported Outcome Measurement Information System (PROMIS) scale, respectively. Linear mixed models evaluated the associations between POS and both burnout and anxiety. A mediation analysis evaluated whether anxiety mediated the POS-burnout association. RESULTS: Of the 538 participants recruited, 402 (75%) were included in the primary analysis. 55% of participants were physicians, 73% 25-44 years of age, 73% female, 83% White, and 44% had ≥1 dependent. Higher POS was significantly associated with a lower risk for burnout (-0.23; 95% CI -0.26, -0.21; p<0.001) and lower degree of anxiety (-0.07; 95% CI -0.09, -0.06; p = 0.010). Anxiety mediated the associated between POS and burnout (direct effect -0.17; 95% CI -0.21, -0.13; p<0.001; total effect -0.23; 95% CI -0.28, -0.19; p<0.001). CONCLUSION: During a health crisis, increasing the organizational support perceived by healthcare employees may reduce the risk for burnout through a reduction in anxiety. Improving the relationship between healthcare organizations and the individuals they employ may reduce detrimental effects of psychological distress among healthcare providers and ultimately improve patient care.

The Prognostic Value of Axillary Staging Following Neoadjuvant Chemotherapy in Inflammatory Breast Cancer.

BACKGROUND: Inflammatory breast cancer (IBC) has historically been characterized by high rates of recurrence and poor survival; however, there have been significant improvements in systemic therapy. We sought to investigate modern treatment of IBC and define the yield and prognostic significance of axillary lymph nodes after neoadjuvant chemotherapy (NAC). METHODS: Women with clinical stage T4d, N0-N3, M0 IBC from 2012 to 2016 in the National Cancer Database were included. Kaplan-Meier survival curves and Cox regression were used to assess mortality by receptor subtype and nodal status. RESULTS: We identified 5265 patients; 37% hormone receptor (HR) +/HER2 - , 19% HR +/HER2 + , 18% HR -/HER2 + , and 26% triple-negative, and 5-year overall survival was 51.6%. Only 34% were treated according to guidelines with NAC, modified radical mastectomy, and adjuvant radiation. Pathologically positive lymph nodes (ypN +) after NAC varied by subtype and clinical nodal status (cN) ranging from 82% in cN + HR +/HER2 - patients to 19% in cN0 HR -/HER2 + patients. ypN + strongly correlated with survival in all subtypes with the most pronounced impact in HR +/HER2 + patients, with 90% 5-year overall survival in ypN0 versus 66% for ypN + (HR 4.29, 95% CI 1.58-11.70, p = 0.03). CONCLUSIONS: Five-year survival in M0 IBC is 51.6%. Positive nodes after NAC varied by subtype and clinical N status but is sufficiently high and provided meaningful prognostication in all subtypes to support continued routine pathologic assessment. Future study is warranted to identify reliable, less morbid, methods of staging the axilla in IBC patients appropriate for deescalation of axillary surgery.

Effects of Gender Bias and Stereotypes in Surgical Training: A Randomized Clinical Trial.

Importance: Factors contributing to underrepresentation of women in surgery are incompletely understood. Pro-male bias and stereotype threat appear to contribute to gender imbalance in surgery. Objectives: To evaluate the association between pro-male gender bias and career engagement and the effect of stereotype threat on skill performance among trainees in academic surgery. Design, Setting, and Participants: A 2-phase study with a double-blind, randomized clinical trial component was conducted in 3 academic general surgery training programs. Residents were recruited between August 1 and August 15, 2018, and the study was completed at the end of that academic year. In phase 1, surveys administered 5 to 6 months apart investigated the association of gender bias with career engagement. In phase 2, residents were randomized 1:1 using permuted-block design stratified by site, training level, and gender to receive either a trigger of or protection against stereotype threat. Immediately after the interventions, residents completed the Fundamentals of Laparoscopic Surgery (FLS) assessment followed by a final survey. A total of 131 general surgery residents were recruited; of these 96 individuals with academic career interests met eligibility criteria; 86 residents completed phase 1. Eighty-five residents were randomized in phase 2, and 4 residents in each arm were lost to follow-up. Intervention: Residents read abstracts that either reported that women had worse laparoscopic skill performance than men (trigger of stereotype threat [A]) or had no difference in performance (protection against stereotype threat [B]). Main Outcomes and Measures: Association between perception of pro-male gender bias and career engagement survey scores (phase 1) and stereotype threat intervention and FLS scores (phase 2) were the outcomes. Intention-to-treat analysis was conducted. Results: Seventy-seven residents (38 women [49.4%]) completed both phases of the study. The association between pro-male gender bias and career engagement differed by gender (interaction coefficient, -1.19; 95% CI, -1.90 to -0.49; P = .02); higher perception of bias was associated with higher engagement among men (coefficient, 1.02; 95% CI, 0.19-2.24; P = .04), but no significant association was observed among women (coefficient, -0.25; 95% CI, -1.59 to 1.08; P = .50). There was no evidence of a difference in FLS score between interventions (mean [SD], A: 395 [150] vs B: 367 [157]; P = .51). The response to stereotype threat activation was similar in men and women (interaction coefficient, 15.1; 95% CI, -124.5 to 154.7; P = .39). The association between stereotype threat activation and FLS score differed by gender across levels of susceptibility to stereotype threat (interaction coefficient, -35.3; 95% CI, -47.0 to -23.6; P = .006). Higher susceptibility to stereotype threat was associated with lower FLS scores among women who received a stereotype threat trigger (coefficient, -43.4; 95% CI, -48.0 to -38.9; P = .001). Conclusions and Relevance: Perception of pro-male bias and gender stereotypes may influence career engagement and skill performance, respectively, among surgical trainees. Trial Registration: ClinicalTrials.gov Identifier: NCT03623009.

Trends in Surgical Axillary Management in Early Stage Breast Cancer in Elderly Women: Continued Over-Treatment.

INTRODUCTION: In the past two decades, three prospective randomized trials demonstrated that elderly women with early stage hormone positive breast cancer had equivalent disease-specific mortality regardless of axillary surgery. In 2016, the Choosing Wisely campaign encouraged patients and providers to reconsider the role of axillary surgery in this population. We sought to identify factors that contribute to adopting non-operative management of the axilla in these patients. MATERIALS AND METHODS: We performed a retrospective analysis of women ≥ 70 years old with cT1/T2, hormone positive invasive ductal carcinoma who underwent partial or total mastectomy, with/without axillary surgery, and did not receive adjuvant chemotherapy from the National Cancer Database from 2004 to 2015. We used multivariable log-binomial regression to model the risk of undergoing axillary surgery across region, care setting, and Charlson-Deyo scores, and analyzed temporal trends using Poisson regression. From 2004 to 2015, 87,342 of 99,940 women who met inclusion criteria (83%) had axillary surgery. Over time, axillary surgery increased from 78% to 88% (p < 0.001). This rise was consistent across region (p = 0.81) and care setting (p = 0.09), but flattened as age increased (p < 0.001). Omitting axillary surgery was more likely in patients treated in New England (RR 0.88, 95% CI 0.86, 0.89) and patients ≥ 85 (RR 0.66, 95% CI 0.65, 0.67). CONCLUSIONS: Axillary surgery continues to be the preferred option of axillary management in elderly women with early stage, clinically node negative, hormone-positive, invasive breast cancer despite no survival benefit. Identifying factors to improve patient selection and dissemination of current recommendations can improve adoption of current evidence on axillary surgery in the elderly.

Nodal positivity decreases with age in women with early-stage, hormone receptor-positive breast cancer.

BACKGROUND: Despite data demonstrating the safety of omitting axillary surgery in older women with early-stage breast cancer, the incidence of axillary surgery remains high. It was hypothesized that the prevalence of nodal positivity would decrease with advancing age. METHODS: The National Cancer Data Base was used to construct a cohort of adult women with early-stage, clinically node-negative, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative breast cancer treated between 2013 and 2015. Multivariable logistic regression was used to assess the relationship between age and nodal positivity, and this was stratified by the axillary surgery category. Modified Poisson regression was used to estimate the proportion of women receiving adjuvant therapy according to age and nodal status. RESULTS: The incidence of axillary surgery among women aged 70 and older (n = 51,917) remained high nationwide (86%). There was a significant decrease in nodal positivity with advancing age in women with early-stage, ER+, clinically node-negative breast cancer from the youngest cohort up to patients aged 70 to 89 years, and this was independent of histologic subtype (ductal vs lobular), race, comorbidities, and socioeconomic factors. Overall, less than 10% of women aged 70 or older who underwent surgery had node-positive disease, regardless of axillary surgery type, and almost 95% of node-positive patients aged 70 or older were at pathological stage N1mi or N1. CONCLUSIONS: Axillary surgery may be safely omitted for many older women with ER+, clinically node-negative, early-stage breast cancer. Nodal positivity declines with advancing age, and this suggests varied biology in older patients versus younger patients.