Clipping the Positive Lymph Node in Patients with Clinically Node Positive Breast Cancer Treated with Neoadjuvant Chemotherapy: Impact on Axillary Surgery in the ISPY-2 Clinical Trial.

BACKGROUND: For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. PATIENTS AND METHODS: We retrospectively analyzed cN+ ISPY-2 patients (2011-2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. RESULTS: Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8-6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4-1.7, p = 0.7; HR 1.8, 95% CI 0.5-6.0, p = 0.3, respectively]. CONCLUSION: Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.

Internal Mammary Lymphadenopathy Does Not Impact Oncologic Outcomes in Patients Treated with Neoadjuvant Chemotherapy: Results from the I-SPY2 Clinical Trial.

BACKGROUND: Internal mammary lymphadenopathy (IML) plays a role in breast cancer stage and prognosis. We aimed to evaluate method of IML detection, how IML impacts response to neoadjuvant chemotherapy (NAC), and oncologic outcomes. METHODS: We evaluated patients enrolled in the I-SPY-2 clinical trial from 2010 to 2022. We captured the radiographic method of IML detection (magnetic resonance imaging [MRI], positron emission tomography/computed tomography [PET/CT], or both) and compared patients with IML with those without. Rates of locoregional recurrence (LRR), distant recurrence (DR) and event-free survival (EFS) were compared by bivariate analysis. RESULTS: Of 2095 patients, 198 (9.5%) had IML reported on pretreatment imaging. The method of IML detection was 154 (77.8%) MRI only, 11 (5.6%) PET/CT only, and 33 (16.7%) both. Factors associated with IML were younger age (p = 0.001), larger tumors (p < 0.001), and higher tumor grade (p = 0.027). Pathologic complete response (pCR) was slightly higher in the IML group (41.4% vs. 34.0%; p = 0.03). There was no difference in breast or axillary surgery (p = 0.41 and p = 0.16), however IML patients were more likely to undergo radiation (68.2% vs. 54.1%; p < 0.001). With a median follow up of 3.72 years (range 0.4-10.2), there was no difference between IM+ versus IM- in LRR (5.6% vs. 3.8%; p = 0.25), DR (9.1% vs. 7.9%; p = 0.58), or EFS (61.6% vs. 57.2%; p = 0.48). This was true for patients with and without pCR. CONCLUSIONS: In this large cohort of patients treated with NAC, outcomes were not negatively impacted by IML. We demonstrated that IML influences treatment selection but is not a poor prognostic indicator when treated with modern NAC and multidisciplinary disease management.

Society of Surgical Oncology Breast Disease Site Working Group Statement on Contralateral Mastectomy: Indications, Outcomes, and Risks.

Rates of contralateral mastectomy (CM) among patients with unilateral breast cancer have been increasing in the United States. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, risks, and benefits of CM since the society's 2017 statement. We held a virtual meeting to outline key topics and then conducted a literature search using PubMed to identify relevant articles. We reviewed the articles and made recommendations based on group consensus. Patients consider CM for many reasons, including concerns regarding the risk of contralateral breast cancer (CBC), desire for improved cosmesis and symmetry, and preferences to avoid ongoing screening, whereas surgeons primarily consider CBC risk when making a recommendation for CM. For patients with a high risk of CBC, CM reduces the risk of new breast cancer, however it is not known to convey an overall survival benefit. Studies evaluating patient satisfaction with CM and reconstruction have yielded mixed results. Imaging with mammography within 12 months before CM is recommended, but routine preoperative breast magnetic resonance imaging is not; there is also no evidence to support routine postmastectomy imaging surveillance. Because the likelihood of identifying an occult malignancy during CM is low, routine sentinel lymph node surgery is not recommended. Data on the rates of postoperative complications are conflicting, and such complications may not be directly related to CM. Adjuvant therapy delays due to complications have not been reported. Surgeons can reduce CM rates by encouraging shared decision making and informed discussions incorporating patient preferences.

Factors Associated With Node-Positive Disease in Estrogen Receptor-Positive Breast Cancer Patients.

INTRODUCTION: Larger tumor size and shorter tumor-to-nipple distance at diagnosis are associated with greater risk of lymph node involvement in breast cancer. However, the relationship between receptor subtype status and lymph node metastasis remains unclear. Our objective was to examine the association between primary tumor size, location, and nodal metastasis across estrogen receptor (ER)+/ progesterone receptor (PR)+/ human epidermal growth factor receptor 2 (HER2)-, ER+/PR-/HER2-, ER+/PR+/HER2+, and ER+/PR-/HER2+ tumors. METHODS: A single-institution retrospective chart review was conducted of breast cancer patients diagnosed between 1998 and 2019 who underwent nodal evaluation during primary surgery. Neoadjuvant chemotherapy, pure ductal carcinoma in situ, inflammatory, recurrent, metastatic, bilateral, multicentric, and multifocal disease were excluded. Descriptive statistics (proportions and frequencies for categorical variables and medians [Q1-Q3] for continuous variables) were used to summarize patient characteristics. Kruskal-Wallis test was applied to test the association of outcome variables and continuous variables. Chi-square test or Fisher exact test was applied to test the association of outcome variables and categorical variables. RESULTS: Six hundred eighteen ER + patients had a median tumor size of 1.7 cm (1.1-2.5 cm). Two hundred ninety six out of 618 (47.9%) were node-positive and 188/618 (30.4%) had axillary dissection. Eighty four point three percent of patients were ER+/PR+/HER2-, 6.31% were ER+/PR-/HER2-, 6.96% were ER+/PR+/HER2+, and 1.13% were ER+/PR-/HER2+. Median tumor size was significantly larger in node-positive cases compared to node-negative cases in ER+/PR+/HER2-, ER+/PR+/HER2+, and ER+/PR-/HER2- subgroups. In ER+/PR+/HER2-patients, median tumor-nipple distance was significantly shorter in node-positive patients compared to node-negative patients. Upper outer quadrant location was significantly associated with nodal positivity in ER+/PR-/HER2- patients. CONCLUSIONS: Across ER + patients, the significance between tumor size, location, and lymph node positivity varied significantly when differentiating by PR and HER2 status.

Factors Predictive of Positive Lymph Nodes for Breast Cancer.

BACKGROUND: Axillary node status is an important prognostic factor in breast cancer. The primary aim was to evaluate tumor size and other characteristics relative to axillary disease. MATERIALS AND METHODS: Single institution retrospective chart review of stage I-III breast cancer patients collected demographic and clinical/pathologic data from 1998-2019. Student's t-test, Chi-squared test (or Fisher exact test if applicable), and logistic regression models were used for testing the association of pN+ to predictive variables. RESULTS: Of 728 patients (mean age 59 yrs) with mean follow up of 50 months, 86% were estrogen receptor +, 10% Her2+, 78% ER+HER2-negative, and 10% triple-negative. In total, 351/728 (48.2%) were pN+ and mean tumor size was larger in pN+ cases compared to pN- cases (mean = 27.7 mm versus 15.5 mm) (p < 0.001). By univariate analysis, pN+ was associated with lymphovascular invasion (LVI), higher grade, Her2, and histology (p < 0.005). Tumor-to-nipple distance was shorter in pN+ compared to pN- (45 mm v. 62 mm; p< 0.001). Age < 60, LVI, recurrence, mastectomy, larger tumor size, and shorter tumor-nipple distance were associated with 3+ positive nodes (p < 0.05). CONCLUSIONS: Larger tumor size and shorter tumor-nipple distance were associated with higher lymph node positivity. Age less than 60, LVI, recurrence, mastectomy, larger tumor size, and shorter tumor-nipple distance were all associated with 3+ positive lymph nodes.

Glutamate decarboxylase-1 is essential for efficient acclimation of Arabidopsis thaliana to nutritional phosphorus deprivation.

Glutamate decarboxylase (GAD) is a Ca2+ -calmodulin-activated, cytosolic enzyme that produces γ-aminobutyrate (GABA) as the committed step of the GABA shunt. This pathway bypasses the 2-oxoglutarate to succinate reactions of the tricarboxylic acid (TCA) cycle. GABA also accumulates during many plant stresses. We tested the hypothesis that AtGAD1 (At5G17330) facilitates Arabidopsis acclimation to Pi deprivation. Quantitative RT-PCR and immunoblotting revealed that AtGAD1 transcript and protein expression is primarily root-specific, but inducible at lower levels in shoots of Pi-deprived (-Pi) plants. Pi deprivation reduced levels of the 2-oxoglutarate dehydrogenase (2-OGDH) cofactor thiamine diphosphate (ThDP) in shoots and roots by > 50%. Growth of -Pi atgad1 T-DNA mutants was significantly attenuated relative to wild-type plants. This was accompanied by: (i) an > 60% increase in shoot and root GABA levels of -Pi wild-type, but not atgad1 plants, and (ii) markedly elevated anthocyanin and reduced free and total Pi levels in leaves of -Pi atgad1 plants. Treatment with 10 mM GABA reversed the deleterious development of -Pi atgad1 plants. Our results indicate that AtGAD1 mediates GABA shunt upregulation during Pi deprivation. This bypass is hypothesized to circumvent ThDP-limited 2-OGDH activity to facilitate TCA cycle flux and respiration by -Pi Arabidopsis.

Tumor Characteristics Associated with Axillary Nodal Positivity in Triple Negative Breast Cancer.

Larger-size primary tumors are correlated with axillary metastases and worse outcomes. We evaluated the relationships among tumor size, location, and distance to nipple relative to axillary node metastases in triple-negative breast cancer (TNBC) patients, as well as the predictive capacity of imaging. We conducted a single-institution, retrospective chart review of stage I-III TNBC patients diagnosed from 1998 to 2019 who underwent upfront surgery. Seventy-three patients had a mean tumor size of 20 mm (range 1-53 mm). All patients were clinically node negative. Thirty-two patients were sentinel lymph node positive, of whom 25 underwent axillary lymph node dissection. Larger tumor size was associated with positive nodes (p < 0.001): the mean tumor size was 14.30 mm in node negative patients and 27.31 mm in node positive patients. Tumor to nipple distance was shorter in node positive patients (51.0 mm) vs. node negative patients (73.3 mm) (p = 0.005). The presence of LVI was associated with nodal positivity (p < 0.001). Tumor quadrant was not associated with nodal metastasis. Ultrasound yielded the largest number of suspicious findings (21/49), with sensitivity of 0.25 and specificity of 0.40. On univariate analysis, age younger than 60 at diagnosis was also associated with nodal positivity (p < 0.002). Comparative analyses with other subtypes may identify biologic determinants.

Surgeon and Radiologist Evaluation of Electromagnetic Chip Localization for Benign and Malignant Breast Lesions.

BACKGROUND: SmartClipTM is a food and drug administration-approved, electromagnetic chip (EMC) localization system that provides three-dimensional navigation for the excision of soft tissue lesions. The purpose of this study was to analyze the accuracy and feasibility of EMC radiologic and surgical localization for benign and malignant breast lesions. PATIENTS AND METHODS: An institutional review board-approved, single institution, prospective study from October 2020 to September 2022 of 38 women undergoing breast conserving surgery with EMC localization of a single lesion > 5 mm on mammogram (MMG) or ultrasound (US) imaging. Surveys from performing breast radiologists and breast surgeons were collected after image-guided localization and surgical excision. RESULTS: Seventy-six survey responses from nine radiologists and four surgeons were received. The deployment needle and EMC were highly visible in 86.8% and 76.3% of procedures, respectively. There was no difficulty in deployment for 92.1% of procedures. The EMC was in the correct location on postdeployment MMG in 97.4% of cases. Three instances of EMC migration occurred, one 1 cm from target lesion. The targeted mass and EMC were within the surgical specimen in 97.4% of cases. On specimen radiograph, 39.5% of the EMCs were 0-1 mm from the center of the target lesion, 18.4% were within 2-4 mm, and 23.7% were within 5-10 mm. Mean operating room time for all cases was 65 min. One case required US to localize the target due to console malfunction. CONCLUSION: There was successful EMC deployment by radiologists with accurate visualization and successful surgical excision in most cases. The EnVisioTM SmartClipTM system is a reproducible and accurate localization method for benign and malignant breast lesions.

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Factors Influencing Lymph Node Positivity in HER2/neu+ Breast Cancer Patients.

Axillary lymph node metastases are a key prognostic factor in breast cancer treatment. Our aim was to evaluate how tumor size, tumor location, and imaging results correlate to axillary lymph node diseases for patients with stage I-III HER2/neu+ breast cancer. This is a single-institution retrospective chart review of female breast cancer patients diagnosed with primary invasive Her2/neu+ breast cancer who were treated with upfront surgical resection from 2000-2021. Of 75 cases, 44/75 (58.7%) had nodal metastasis, and there was a significant association of larger tumor size to nodal metastases (p ≤ 0.001). Patients with negative nodes had a smaller mean tumor size (n = 30; 15.10 mm) than patients with positive nodes (n = 45; 23.9 mm) (p = 0.002). Preoperative imaging detected suspicious nodes in 36 patients, and ultrasound detected the most positive nodes (14/18; p = 0.027). Our data confirms that tumor size at diagnosis is correlated with a higher likelihood of axillary involvement in patients with Her2/neu+ breast cancer; notably, a large proportion of Her2/neu+ breast cancers have metastatic involvement of axillary lymph nodes even with small primary lesions.

Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial.

Talimogene laherparepvec (T-VEC) is an oncolytic virus hypothesized to enhance triple-negative breast cancer (TNBC) responses to neoadjuvant chemotherapy (NAC). This article describes the phase 2 trial of T-VEC plus NAC (ClinicalTrials.gov ID: NCT02779855 ). Patients with stage 2-3 TNBC received five intratumoral T-VEC injections with paclitaxel followed by doxorubicin and cyclophosphamide and surgery to assess residual cancer burden index (RCB). The primary end point was RCB0 rate. Secondary end points were RCB0-1 rate, recurrence rate, toxicity and immune correlates. Thirty-seven patients were evaluated. Common T-VEC toxicities were fevers, chills, headache, fatigue and injection site pain. NAC toxicities were as expected. Four thromboembolic events occurred. The primary end point was met with an estimated RCB0 rate = 45.9% and RCB0-1 descriptive rate = 65%. The 2-year disease-free rate is equal to 89% with no recurrences in RCB0-1 patients. Immune activation during treatment correlated with response. T-VEC plus NAC in TNBC may increase RCB0-1 rates. These results support continued investigation of T-VEC plus NAC for TNBC.

Intraoperative Fluorescence Guidance for Breast Cancer Lumpectomy Surgery.

BACKGROUND: Although lumpectomy and mastectomy provide equivalent survival for patients with breast cancer, local recurrence after lumpectomy increases breast cancer mortality. Positive lumpectomy margins, which imply incomplete tumor removal, are the strongest predictor of local recurrence and are identified days after surgery, necessitating a second surgery. METHODS: In this prospective trial, we assessed margin status with or without pegulicianine fluorescence-guided surgery (pFGS) for stages 0 to 3 breast cancers. To prevent surgeons from performing smaller than standard lumpectomies in anticipation of pFGS assistance, patients were randomly assigned 10:1 to pFGS or control groups, thus randomization was not designed to provide a control group for evaluating device performance. In patients undergoing pFGS, additional pFGS-guided cavity margins were excised at sites of pegulicianine signal. We evaluated three coprimary end points: the percentage of patients for whom pFGS-guided margins contained cancer, sensitivity, and specificity. RESULTS: Overall, 406 patients received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Among 392 patients randomly assigned, 316 had invasive cancers, and 76 had in situ cancers. In 27 of 357 patients undergoing pFGS, pFGS-guided margins removed tumor left behind after standard lumpectomy, 22 from cavity orientations deemed negative on standard margin evaluation. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins. On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. Pegulicianine administration was stopped for adverse events in six patients. Two patients had grade 3 serious adverse events related to pegulicianine. CONCLUSIONS: The use of pFGS in breast cancer surgery met prespecified thresholds for removal of residual tumor and specificity but did not meet the prespecified threshold for sensitivity. (Funded by Lumicell, Inc. and the National Institutes of Health; Clinicaltrials.gov number, NCT03686215.)

Plant nutrition: An architect of nitrate-hunger cues.

Nitrate perception and uptake are critical for plant well-being. A known actor in nitrate signaling, the transcription factor NLP7, has now been reported to have a new role: as a nitrate sensor. The latter function has been characterized and exploited to generate a fluorescent nitrate biosensor.

Surgical Management of the Axilla in Invasive Lobular Carcinoma in the Z1071 Era: A Propensity-Score Matched Analysis of the National Cancer Database.

In patients with invasive lobular carcinoma (ILC) and clinically positive nodes (cN1) who demonstrate an axillary clinical response to neoadjuvant-chemotherapy (NAC), the outcomes of sentinel lymph node biopsy (SLNB) compared to axillary lymph node dissection (ALND) are not well studied. We sought to evaluate axillary surgery practice patterns and the resultant impact on overall survival (OS) in cN1 ILC. The National Cancer Database (NCDB) was queried (2012-2017) for women with cN1 ILC who were treated with NAC followed by surgery. Propensity-score matching was performed between SLNB and ALND cohorts. Kaplan-Meier and Cox regression analyses were performed to identify predictors of OS. Of 1390 patients, 1192 were luminal A ILCs (85.8%). 143 patients (10.3%) had a complete axillary clinical response, while 1247 (89.7%) had a partial clinical response in the axilla. Definitive axillary surgery was SLNB in 211 patients (15.2%). Utilization of SLNB for definitive axillary management increased from 8% to 16% during the study period. Among 201 propensity-score matched patients stratified by SLNB vs. ALND, mean OS did not significantly differ (81.6 ± 1.8 vs. 81.4 ± 2.0 months; p = 0.56). Cox regression analysis of the entire cohort demonstrated that increasing age, grade, HER2+ and triple-negative tumors, and partial clinical response were unfavorable OS predictors (p < 0.02 each). The definitive axillary operation and administration of adjuvant axillary radiation did not influence OS. In cN1 ILC patients with a clinical response to NAC in the axilla, SLNB vs. ALND did not affect OS. Further axillary therapy may be warranted with ypN+ disease.