Pre-treatment peripheral blood immunophenotyping and response to neoadjuvant chemotherapy in operable breast cancer.

BACKGROUND: Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied. METHODS: Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal-Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC. RESULTS: There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (TEMRA) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response. CONCLUSIONS: Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + TEMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer. TRIAL REGISTRATION: NCT02022202 . Registered 20 December 2013.

Nodal pCR and overall survival following neoadjuvant chemotherapy for node positive ER+/Her2- breast cancer.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in node-positive (N+) ER+/HER2- breast cancer (BC) is debated, given low total pathologic complete response (pCR) rates. However, the rate and impact of nodal pCR is unknown. We sought to evaluate nodal pCR rates and the impact on overall survival (OS). Further, we sought to validate the association between nodal pCR with age and Ki67. METHODS: We queried the National Cancer Database for cN + ER+/HER2- BC patients treated with NAC and surgery. Data from 2010 to 2018 were used to evaluate nodal pCR and OS, with multivariable Cox proportional hazards modeling for OS, as well as Ki67 for the years 2018-2019. RESULTS: From 2010 to 2018, we identified 19,611 cN + ER+/HER2- BC patients treated with NAC. While total pCR occurred in only 7.4%, nodal pCR rates were nearly double (14.3%). Nodal pCR (+/- breast pCR) was seen in 21.7% and associated with 5-year OS rate of 86.1% (95% CI: 84.9-87.4%) versus 77.1% (95% CI: 76.3-77.9%) in patients without nodal pCR (p < 0.001). On multivariable analysis, nodal pCR had better OS (adjusted HR 0.57, 95% CI 0.52-0.63, p < 0.001) across all age groups. Of 2,444 patients with available Ki67, those with age < 50 and Ki67 ≥ 20% had the highest nodal pCR at 31.6%. CONCLUSION: In cN + ER+/HER2- BC treated with NAC, nodal pCR is common, associated with age and Ki67, and prognostic for OS. These data strongly suggest that for cN + patients, eradication of nodal disease is critical for OS, and total pCR may not be the optimal measure of NAC benefit.

Tumor Characteristics of Bilateral Breast Cancer Compared with Unilateral Breast Cancer.

BACKGROUND: Bilateral breast cancer (BC) has an incidence of 1 to 3 %. This study aimed to describe the clinicopathologic characteristics and management of bilateral BC, estimate disease-free survival (DFS), and compare DFS with unilateral BC. METHODS: A retrospective analysis was performed for patients who had bilateral invasive BC or unilateral invasive BC and contralateral ductal carcinoma in situ (DCIS) treated at Mayo Clinic Rochester from 2008 to 2022. A 4:1 matched cohort of patients with unilateral invasive BC was used for comparison. The groups were compared using Wilcoxon rank-sum or chi-square tests. Disease-free survival was analyzed using the Kaplan-Meier method and log-rank test, with Cox proportional hazards regression used for multivariable analysis. RESULTS: The study identified 278 cases of bilateral breast cancer (177 cases of bilateral invasive cancer and 101 cases of unilateral invasive cancer with contralateral DCIS), representing 4.1 % of invasive BCs. Biologic subtype was concordant between sides in 79.8 % of the patients. Initial surgery was bilateral mastectomy for 76.6 %, bilateral lumpectomy for 20.5 %, and unilateral mastectomy with unilateral lumpectomy for 2.9 % of the patients. Pathogenic variants in breast cancer predisposition genes were present in 21.7 % of those tested. The patients who had bilateral BC presented with a higher cT category than the patients who had unilateral BC (p = 0.02), and a higher proportion presented with ILC (17.3 % vs 10.9 %; p = 0.004), estrogen receptor-positive (ER+) disease (89.2 % vs 84.2 %; p = 0.04), multicentric/multifocal disease (37.1 % vs 24.3 %; p < 0.001), breast cancer pathogenic variant (21.7 % vs 12.4 %; p = 0.02), and palpable presentation (48.2 % vs 40.8 %; p = 0.03). The patients with bilateral BC showed DFS similar to that for the unilateral BC cohort (p = 0.71). CONCLUSIONS: Bilateral BCs most commonly are biologically concordant between sides. Bilateral BC presented more commonly with larger tumors, lobular histology, ER+ status, multicentricity or multifocality, pathogenic variant, and palpable disease. Bilateral BC is not associated with worse DFS than unilateral BC.

Impact of Presenting Stage on Overall Survival in Patients Treated with Neoadjuvant Chemotherapy for Triple Negative Breast Cancer.

PURPOSE: For operable triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), clinical prognostication and postoperative decision-making relies exclusively on whether a pathologic complete response (pCR) is achieved or not. We evaluated whether extent of disease at presentation further influenced overall survival (OS) among patients with pCR or with residual disease (RD) following NAC. METHODS: Patients with stage I-III TNBC who underwent NAC were identified from the National Cancer Database from 2010 to 2019. Overall survival was assessed by disease extent using the Kaplan-Meier method and Cox proportional hazards regression for univariate and multivariable analysis. RESULTS: A total of 35,598 patients met inclusion criteria, and 11,967 achieved pCR. Ten-year OS was 88.5% and varied by cT and cN category at presentation. Best 10-year OS was seen in patients with cT1-2, cN0 (90.9%) and was worst in those with cT3-4, cN2-3 disease (72.0%). A total of 23,631 patients had RD. Ten-year OS was 60.1% and varied by cT and cN category at presentation. Best 10-year OS was seen in patients with cT1-2, cN0 (73.0%) and was worst in those with cT3-4, cN2-3 disease (36.3%). Notably, OS was significantly poorer for patients with cT3-4, cN2-3 disease at diagnosis and pCR versus those with cT1-2 cN0 and RD (aHR 1.30, 95% confidence interval 1.03-1.63, p = 0.03). CONCLUSIONS: Among patients with TNBC, extent of disease at presentation was prognostic for OS independently of response to NAC. Patients with advanced stage at presentation had poorer OS even in the context of pCR. Further investigation is needed to evaluate whether additional adjuvant therapy strategies should be considered for these patients.

ASO Author Reflections: Toward Individualized Management of Heterogenous Mixed Invasive Ductolobular Breast Cancers.

Mixed invasive ductolobular breast cancer (MIDLC) is a rare breast cancer with varying lobular and ductal components. Characteristics, management, and outcomes of MIDLC are not well understood due to the rarity of the cancer and the lack of uniform diagnostic criteria and reporting. There is a need for better understanding and individualized management of this heterogeneous spectrum of breast cancers.

Lobular-Like Features and Outcomes of Mixed Invasive Ductolobular Breast Cancer (MIDLC): Insights from 54,403 Stage I-III MIDLC Patients.

BACKGROUND: Mixed invasive ductolobular breast cancer (MIDLC) is a rare histological subtype of breast cancer (BC), with components of both invasive ductal cancer (IDC) and invasive lobular cancer (ILC). Its clinicopathological features and outcomes have not been well characterized. METHOD: The National Cancer Database 2010-2017 was reviewed to identify women with stage I-III BCs. Univariate analysis was performed using Chi-square or Wilcoxon rank-sum tests and multivariable analysis with logistic regression to predict surgical decisions. Survival was assessed using multivariable Cox proportional hazards regression analysis. RESULTS: We identified 955,828 women with stage I-III BCs (5.7% MIDLC, 10.3% ILC, and 84.0% IDC). MIDLC was more like ILC than IDC in terms of multicentricity (14.2% MIDLC, 13.0% ILC, 10.0% IDC), hormone receptor positivity (96.6% MIDLC, 98.2% ILC, 81.2% IDC), and use of neoadjuvant chemotherapy (NAC; 5.8% MIDLC, 5.2% ILC, 10.8% IDC). 744,607 women underwent upfront surgery. The mastectomy rates were 42.3% for MIDLC, 46.5% for ILC, and 33.3% for IDC (all p < 0.001). With 5.5 years of median follow-up, the adjusted overall survival in the upfront surgery hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) biological subgroup was better in MIDLC (hazard ratio 0.88, p < 0.001) and ILC (hazard ratio 0.91, p < 0.001) than in IDC. Like ILC, MIDLC also had a lower pathological complete response to NAC than IDC (12.3% MIDLC, 7.3% ILC, 28.6% IDC). CONCLUSIONS: MIDLC displays a mixed pattern of characteristics favoring features of ILC compared with IDC, with favorable 5-year overall survival compared with IDC within the HR+/HER2- subtype who underwent upfront surgery.

Repeat sentinel lymph node surgery for locally recurrent breast cancer after prior mastectomy.

BACKGROUND AND OBJECTIVES: Current NCCN guidelines discourage repeat sentinel lymph node (SLN) surgery in patients with local recurrence (LR) of breast cancer following prior mastectomy. This study addresses the feasibility and therapeutic impact of this approach. METHODS: We identified 73 patients managed with repeat SLN surgery for post-mastectomy isolated LR. Lymphatic mapping was performed using radioisotope with or without lymphoscintigraphy and/or blue dye. Successful SLN surgery was defined as retrieval of ≥1 SLN. RESULTS: SLN surgery was successful in 65/73 (89%), identifying a median of 2 (range 1-4) SLNs, with 10/65 (15%) SLN-positive. Among these, 5/10 (50%) proceeded to ALND. In unsuccessful cases, 1/8 (13%) proceeded to ALND. Seven of 10 SLN-positive patients and 50/55 SLN-negative patients received adjuvant radiotherapy. Chemotherapy was administered in 31 (42%) and endocrine therapy in 50 of 57 HR+ patients (88%). After 28 months median follow-up, eight patients relapsed with the first site local in two, distant in five, and synchronous local/distant in one. No nodal recurrences were observed. CONCLUSIONS: SLN surgery for patients with LR post-mastectomy is feasible and informative. This approach appears oncologically sound, decreases axillary dissection rates and may be used to tailor adjuvant radiation target volumes and systemic therapies.

Immune cells are increased in normal breast tissues of BRCA1/2 mutation carriers.

PURPOSE: Breast cancer risk is elevated in pathogenic germline BRCA 1/2 mutation carriers due to compromised DNA quality control. We hypothesized that if immunosurveillance promotes tumor suppression, then normal/benign breast lobules from BRCA carriers may demonstrate higher immune cell densities. METHODS: We assessed immune cell composition in normal/benign breast lobules from age-matched women with progressively increased breast cancer risk, including (1) low risk: 19 women who donated normal breast tissue to the Komen Tissue Bank (KTB) at Indiana University Simon Cancer Center, (2) intermediate risk: 15 women with biopsy-identified benign breast disease (BBD), and (3) high risk: 19 prophylactic mastectomies from women with germline mutations in BRCA1/2 genes. We performed immunohistochemical stains and analysis to quantitate immune cell densities from digital images in up to 10 representative lobules per sample. Median cell counts per mm2 were compared between groups using Wilcoxon rank-sum tests. RESULTS: Normal/benign breast lobules from BRCA carriers had significantly higher densities of immune cells/mm2 compared to KTB normal donors (all p < 0.001): CD8 + 354.4 vs 150.9; CD4 + 116.3 vs 17.7; CD68 + 237.5 vs 57.8; and CD11c + (3.5% vs 0.4% pixels positive). BBD tissues differed from BRCA carriers only in CD8 + cells but had higher densities of CD4 + , CD11c + , and CD68 + immune cells compared to KTB donors. CONCLUSIONS: These preliminary analyses show that normal/benign breast lobules of BRCA mutation carriers contain increased immune cells compared with normal donor breast tissues, and BBD tissues appear overall more similar to BRCA carriers.

Clinical Behavior, Management, and Treatment Response of Estrogen Receptor Low (1-10%) Breast Cancer.

INTRODUCTION: Estrogen receptor (ER) and progesterone receptor (PR) guide management and impact outcomes of breast cancer (BC). This study compares ER-low (1-10%) with ER-negative (< 1%) and ER-positive (>10%) BC and investigates the significance of PR expression within ER-low disease. PATIENTS AND METHODS: All patients with HER2-negative invasive BC were identified from the National Cancer Database 2018-2019. Treatment and outcomes were compared using chi-squared tests and multivariable logistic regression. RESULTS: Of 232,762 patients, ER expression was: negative (13.8%), low (2.0%), and > 10% (84.2%). Chemotherapy was given in 83.9% of ER- disease, 82.4% of ER-low/PR- disease, 58.9% of ER-low/PR+ disease, and only in 22.9% of ER+ disease. Within the ER-low subgroup, adjuvant endocrine therapy, recurrence score, and Ki67 varied by PR status (all < 0.01). Patients with ER-low disease selected for neoadjuvant chemotherapy (NAC) were younger and had higher T and N category, tumor grade, and Ki67. With NAC, pathological complete response (pCR) rates were similar between ER-low/PR- and ER-low/PR+ (39.5% and 38.1%, respectively, p = 0.67), and were closer to the ER- group (39.7%) than the ER+ group (8.4%). On multivariable analysis, the adjusted effect of ER status (1-10% versus > 10%) on chemotherapy administration was odds ratio (OR) 8.2 (95% CI 7.3-9.2, p < 0.001) for PR-negative, and OR 3.3 (95% CI 7.3-9.2, p < 0.001) for PR-positive. CONCLUSIONS: This study suggests that the tumor features and clinical management of ER-low tumors vary significantly by PR expression. Within ER-low tumors, PR- tumors more closely resemble ER- BC, while PR+ tumors exhibit less aggressive characteristics. In ER-low disease selected for treatment with NAC, response is similar to ER- regardless of PR status.

Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients.

BACKGROUND: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. METHODS: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. FINDINGS: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41-1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79-2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36-1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73-2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes). INTERPRETATION: RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy. FUNDING: National Cancer Institute at the US National Institutes of Health.

Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence.

BACKGROUND: Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. METHODS: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher's exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models. RESULTS: Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. CONCLUSIONS: Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

Serum hormone levels and normal breast histology among premenopausal women.

PURPOSE: Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations. METHODS: Pathology AI analysis was performed on 316 digital images of H&E-stained sections of normal breast tissues from Komen Tissue Bank donors ages ≤ 45 years to assess 11 quantitative metrics. Associations of circulating factors with AI metrics were assessed using regression analyses, with inclusion of interaction terms to assess effect modification. RESULTS: Higher prolactin levels were related to larger TDLU area (p < 0.001) and increased presence of adipose tissue proximate to TDLUs (p < 0.001), with less significant positive associations for acini counts (p = 0.012), dilated acini (p = 0.043), capillary area (p = 0.014), epithelial area (p = 0.007), and mononuclear cell counts (p = 0.017). Testosterone levels were associated with increased TDLU counts (p < 0.001), irrespective of parity, but associations differed by adipose tissue content. AI data for TDLU counts generally agreed with prior visual assessments. CONCLUSION: Among premenopausal women, serum hormone levels linked to BC risk were also associated with quantitative features of normal breast tissue. These relationships were suggestively modified by parity status and tissue composition. We conclude that the microanatomic features of normal breast tissue may represent a marker of BC risk.

Neoadjuvant Chemotherapy and Nodal Response Rates in Luminal Breast Cancer: Effects of Age and Tumor Ki67.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is standard for most triple-negative and human epidermal growth factor receptor 2 (HER2)+ breast cancers, and frequently downstages node-positive (cN+) disease, permitting omission of axillary dissection. In estrogen receptor (ER)+/HER2- disease, response rates are lower. Whether Ki67 is associated with axillary downstaging in ER+/HER2- disease is unknown. METHODS: With institutional review board approval, we queried our institutional database to identify all patients with primary ER+/HER2- biopsy-proven cN+ breast cancer treated with NAC followed by surgery from January 2012 to December 2021. Nodal pathologic complete response (pCR) rates were evaluated by pretreatment Ki67 and patient age. RESULTS: 315 patients (median age 50 years) were included. Nodal pCR rate was 24.8% (78/315) and was higher in patients aged < 50 years than ≥ 50 years (31.8% versus 17.7%, p = 0.004). Ki67 was available on 236 patients (74.9%). Median Ki67 was 29.0% (range 1-98%) and did not differ by age category (p = 0.23). Patients with nodal pCR had higher Ki67 (median 40.3% versus 25.0%, p < 0.001). Nodal pCR rates were 28.4% (Ki67 ≥ 20%) versus 8.1% (Ki67 < 20%) (p < 0.001). On multivariable analysis, Ki67 and age category were predictive of nodal pCR. Combining these two parameters together, nodal pCR rates in age < 50 years were 35.8% when Ki67 ≥ 20% versus 14.3% with Ki67 < 20% (p = 0.02). In contrast, for age ≥ 50 years, nodal pCR was 21.0% for Ki67 ≥ 20% versus 2.6% with Ki67 < 20% (p = 0.008). CONCLUSIONS: In ER+/HER2- breast cancer, nodal downstaging with NAC is associated with age (< 50 years) and Ki67 (≥ 20%). Age and Ki67 should be considered for NAC decision-making and can identify patients with high rates of nodal downstaging (36%) who would benefit from NAC to enable axillary preservation.

Nodal Pathologic Complete Response Rates in Luminal Breast Cancer Vary by Genomic Risk.

BACKGROUND: Although an advantage of neoadjuvant chemotherapy (NAC) is eradication of axillary disease, nodal pCR rates are much lower for ER+/HER2- breast cancer than other subtypes. We sought to evaluate the association of genomic risk with nodal pCR in ER+/HER2- disease. METHODS: Patients with ER+/HER2- clinically-node-positive (cT0-cT4d/cN1-cN3/cM0) breast cancer treated with NAC and surgery 2010-2018 in the National Cancer Database were identified. Low genomic risk was classified as Oncotype Dx Recurrence Score (RS) 0-25, or Mammaprint 70-gene or RS coded as "Low." High genomic risk included RS >25, or 70-gene or RS coded as "High." Nodal pCR was compared between patients with high versus low genomic risk by using chi-square tests and multivariable logistic regression. RESULTS: Of 15,698 patients, genomic risk was available for 692 of 15,698 (4.4%). High genomic risk was similar between patients aged <50 years versus 50+ (50.8% vs. 57.3%, p = 0.10). Nodal pCR was higher in high genomic risk (25.0%) than low genomic risk (10.4%, p < 0.001). This difference was observed both for patients aged <50 years (29.9% vs. 9.8%) and aged ≥50 years (22.7% vs. 10.8%). On multivariable analysis adjusted for potential confounding variables, including age, grade, and PR status, genomic risk was independently associated with decreased odds of residual nodal disease (odds ratio 0.49, p = 0.002). CONCLUSIONS: For patients with node-positive ER+/HER2- breast cancer treated with NAC, nodal pCR was highest in patients aged <50 years with high genomic risk tumors. In contrast, nodal pCR rates were low in patients with low genomic risk tumors, regardless of age. This information may help when counseling patients regarding axillary management.

Factors Influencing Non-sentinel Lymph Node Involvement in Patients with Positive Sentinel Lymph Node(s) After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: When a positive sentinel lymph node (SLN) is identified after neoadjuvant chemotherapy (NAC), completion axillary lymph node dissection (cALND) is generally recommended. We sought to evaluate the rate of non-SLN positivity and factors influencing this in patients with a positive SLN following NAC. METHODS: We identified all patients at our hospital between 2006 and 2021 with a positive SLN (> 0.2 mm) following NAC who underwent cALND. Rates of positive non-SLN (NSLN) on cALND were compared by nodal status. Chi-square tests and multivariable logistic regression were used to assess factors predictive of positive NSLN and overall nodal burden. RESULTS: Overall, 229 cases (177 cN+, 52 cN0 prior to NAC) with positive SLN(s) after NAC underwent cALND. Additional NSLN involvement was found in 129/229 (56.3%) patients, including 24/52 (46.2%) cN0 and 105/177 (59.3%) cN+ patients (p = 0.09). There was a trend for patients with SLN micrometastases to be less likely to have positive NSLN(s) than those with SLN macrometastases (38.5% vs. 58.6%; p = 0.05). Subgroup analyses showed no clinicopathologic factors significantly associated with additional axillary involvement for initially cN0 patients. Factors found to significantly influence NSLN positivity in the initially cN+ subgroup were HER2 status, multicentricity/multifocality, number of positive SLNs, and size of SLN metastasis. SLN metastasis size > 5 mm and three or more positive SLNs exerted the greatest influence on NSLN positivity. CONCLUSION: Rates of nodal positivity on cALND in the setting of positive SLN after NAC are high, supporting the current standard of routine cALND. In cN+ disease, NSLN positivity varies by tumor biology, multicentricity/multifocality, number of positive SLNs, and SLN metastasis size.

Contemporary Axillary Management in cT1-2N0 Breast Cancer with One or Two Positive Sentinel Lymph Nodes: Factors Associated with Completion Axillary Lymph Node Dissection Within the National Cancer Database.

BACKGROUND: Management of the axilla in patients with cT1-2N0 breast cancer with one or two positive (+) sentinel lymph nodes (SLNs) is often debated, especially in patients undergoing mastectomy. In 2018, the National Cancer Database (NCDB) began collecting the number of +SLNs, enabling identification of patients with one or two +SLNs for the first time. METHODS: From the 2018 NCDB participant user file (PUF), all cT1-2N0M0 patients with one or two +SLNs were identified. The rates of completion axillary lymph node dissection (cALND) after breast-conserving surgery (BCS) and mastectomy were determined, and logistic regression was used to assess factors associated with cALND. RESULTS: Of 10,531 patients with one or two +SLNs, cALND was performed in 807/6498 (12.4%) BCS patients and 1845/4033 (45.7%) mastectomy patients (p < 0.001). Factors associated with cALND in BCS were cT2 versus cT1 (16.0% versus 11.1%, p < 0.001), two versus one positive SLN (20.7% versus 10.8%, p < 0.001), and higher tumor grade (grade 3: 15.4% versus grade 1-2: 11.7%, p = 0.002). Factors associated with cALND among mastectomy were cT2 versus cT1 (48.2% versus 43.7%, p = 0.004), two versus one positive SLN (56.6% versus 42.8%, p < 0.001), younger age (age < 50 years: 49.0%, age 50+ years: 44.1%, p = 0.004), and Hispanic ethnicity (55.7% versus 45.1%, p = 0.001). After adjusting for pN category, adjuvant radiation was significantly less likely after mastectomy if cALND was performed (odds ratio (OR) 0.51, p < 0.001). CONCLUSIONS: Omission of cALND with one or two +SLNs in BCS is common. Deescalation of axillary therapy in mastectomy is slower, with a cALND rate of 45.7% in 2018. With the recent updates to the National Cancer Care Network (NCCN) guidelines, we anticipate continued deescalation of axillary therapy in mastectomy patients.

Overuse of Axillary Surgery in Patients with Ductal Carcinoma In Situ: Opportunity for De-escalation.

BACKGROUND: Ductal carcinoma in situ (DCIS) is noninvasive breast cancer and therefore nodal staging is not routinely recommended. We evaluated the use of and factors associated with axillary surgery in DCIS in the National Cancer Database (NCDB). METHODS: DCIS cases were identified from the NCDB 2012-2018. Use of axillary surgery was evaluated over time, and factors associated with axillary surgery were assessed for breast-conserving surgery (BCS) and mastectomy groups. RESULTS: We identified 178,762 patients, median age of 60 years. Majority of DCIS (87%) was ER-positive, and 14% low, 43% intermediate, and 44% high grade. Median DCIS size was 1.1 cm. BCS was performed in 72%, whereas 28% had mastectomy. Overall axillary surgery was performed in 38% and was higher in patients undergoing mastectomy compared with patients undergoing BCS (88% vs. 19%, p < 0.001). At axillary surgery, the vast majority (92%) had 1-5 nodes examined, whereas 8% had >5 nodes examined. Over time, axillary surgery decreased in BCS patients (21% in 2012 to 17% in 2018, p < 0.001) but increased slightly in mastectomy patients (86% in 2012 to 90% in 2018, p < 0.001). On multivariable analysis, factors significantly associated with axillary surgery were younger patient age, larger tumor size, higher grade, and ER-negative status. CONCLUSIONS: Factors associated with axillary surgery reflect higher risk disease for upstage to invasive cancer, indicating surgeon judgment. However, despite axillary surgery being overtreatment of DCIS, it is common in mastectomy and is performed for one in five patients undergoing BCS. This provides opportunity for improvement in breast cancer care delivery.

Lack of Clinical Value for Immunohistochemistry for Sentinel Lymph Node Assessment in Invasive Lobular Carcinoma.

BACKGROUND: The distinct histologic appearance of invasive lobular carcinoma (ILC) may pose diagnostic challenges for sentinel lymph node (SLN) analysis. We evaluated the impact of cytokeratin immunohistochemistry (IHC) on SLN assessment in ILC and its contribution to pathologic nodal upstaging. METHODS: We identified ILC patients treated with SLN surgery at our institution between September 2008 and August 2021. IHC for SLN assessment was employed at the discretion of the pathologist. Differences between groups evaluated with and without IHC were compared using Chi-square tests. RESULTS: Overall, 608 cases of ILC were identified in patients who underwent SLN surgery. IHC was used in 301 cases (49.5%) and was not associated with cT category, pT category, or tumor grade. Use of IHC increased detection of SLN+ disease when isolated tumor cells (ITCs) were included in the analysis (35.9% with IHC vs. 21.2% without IHC; p < 0.001). There was no effect on nodal upstaging to micrometastatic disease (pN1mi) or greater (21.9% with IHC vs. 21.2% without IHC; p = 0.82). IHC did not increase the number of positive SLNs detected (median 1 with and without IHC) nor did it increase axillary lymph node dissection (ALND) rates (11.6% with IHC vs. 15.3% without IHC; p = 0.18). CONCLUSION: IHC improved detection of pN0(i+) disease among ILC patients undergoing SLN surgery. IHC did not increase upstaging to pN1mi or higher categories of nodal disease, detection of a greater number of positive SLNs, or ALND rates. Our data suggest routine use of IHC for SLN assessment in ILC patients does not add clinical utility.

Impact of the COVID-19 Pandemic on Breast Cancer Stage at Diagnosis, Presentation, and Patient Management.

INTRODUCTION: The COVID-19 pandemic caused delays in breast cancer management forcing clinicians to potentially alter treatment recommendations. This study compared breast cancer stage at diagnosis and rates of neoadjuvant therapy among women presenting to our institution before and during COVID-19. METHODS: Retrospective chart review of patients with a new breast cancer diagnosis from March 2020-August 2020 (during-COVID-19) were compared with March 2019-August 2019 (pre-COVID-19). We compared stage at diagnosis, clinical/demographic features, and neoadjuvant therapy use between the time periods. RESULTS: A total of 573 patients included: 376 pre-COVID-19, 197 during-COVID-19. Method of cancer detection was by imaging in 66% versus 63% and by physical findings/symptoms in 34% versus 37% of patients comparing pre-COVID-19 to during-COVID-19, p = 0.47. Overall clinical prognostic stage did not differ significantly (p = 0.39) between the time periods, nor did cM1 disease (2% in each period); 23% pre-COVID-19 and 27% during-COVID-19 presented with cN+ disease (p = 0.38). Neoadjuvant therapy use was significantly higher during-COVID-19 (39%) versus pre-COVID-19 (29%, p = 0.02) driven by increased neoadjuvant endocrine therapy (NET) use (7% to 16%, p = 0.002), whereas neoadjuvant chemotherapy use did not change (22% vs. 23%, p = 0.72). In HR+/HER2- disease, NET use increased from 10% pre-COVID-19 to 23% during-COVID-19 (p = 0.001) with a significant increase in stage I patients (7 to 22%, p < 0.001) and nonsignificant increases in stage II (18 to 23%, p = 0.63) and stage III (9 to 29%, p = 0.29). CONCLUSIONS: Breast cancer stage at diagnosis did not differ significantly during-COVID-19 compared with pre-COVID-19. More patients during-COVID-19 were treated with NET, which was significantly increased in stage I HR+/HER2- disease.

Sexual Well-Being After Nipple-Sparing Mastectomy: Does Preservation of the Nipple Matter?

INTRODUCTION: The primary aim of this study was to evaluate patient-reported outcome measures in patients undergoing mastectomy with and without breast reconstruction (immediate or delayed) with and without nipple preservation. METHODS: All female patients undergoing mastectomy between 2011 and 2015 at Mayo Clinic Rochester were identified and were mailed the BREAST-Q survey. Breast satisfaction, psychosocial well-being, and sexual well-being were evaluated and compared by surgery type using Wilcoxon rank-sum tests for univariate analysis and linear regression for multivariable analysis adjusting for potential confounders. RESULTS: Of 1547 patients, 771 completed the BREAST-Q survey (response rate 50%). Of these 771 respondents, 237 (31%) did not have reconstruction, 198 (26%) had nipple-sparing mastectomy with reconstruction (NSM), and 336 (44%) had skin-sparing mastectomy with reconstruction (SSM) ± nipple-areolar complex (NAC) reconstruction (via surgery ± tattoo). Patients with breast reconstruction had consistently higher BREAST-Q scores versus those without. Comparing NSM with all SSMs, there was no difference in satisfaction with breasts (mean 71.8 vs. 70.2, p = 0.21) or psychosocial well-being (mean 81.9 vs. 81.3, p = 0.47); however, sexual well-being was significantly higher in the NSM group on univariate (mean 64.5 vs. 58.0, p = 0.002) and multivariable (ß = -4.69, p = 0.03) analysis. Sexual well-being scores were similar for NSM and the SSM subgroups with any type of NAC reconstruction. CONCLUSIONS: This study demonstrates that NSM positively impacts patient sexual well-being after breast reconstruction compared with SSM, particularly SSM without nipple reconstruction or tattoo. SSM with any type of NAC reconstruction achieved similar satisfaction and sexual well-being to those undergoing NSM.