Nodal pCR Research Articles

Immunohistochemical Status Predicts Pathologic Complete Response to Neoadjuvant Therapy in HER2-Overexpressing Breast Cancers.

Human epidermal growth factor receptor 2 (HER2) overexpression (HER2+) is defined by immunohistochemistry (IHC) and in situ hybridization (ISH) as IHC3+ or IHC2+/ISH+. Response differences to neoadjuvant anti-HER2 therapy (NT) in IHC3+ versus IHC2+/ISH+ breast cancer patients are poorly characterized. We explored whether pathologic complete response (pCR) varies by HER2 IHC status. Patients with stage I-III HER2+ breast cancer undergoing NT and surgery between 2013 and 2020 were identified from the National Cancer Database and stratified by IHC status. Breast and nodal pCR were analyzed. Of 40,711 HER2+ patients, 83% were IHC3+ and 17% were IHC2+/ISH+. IHC3+ patients were more likely to be hormone receptor (HR)-negative (33 vs. 21%), have cT3/4 tumors (24 vs. 21%), and be cN+ (52 vs. 47%; all p < 0.0001). Breast conservation rates were similar (each 43%, p = 0.32), although IHC3+ axillary lymph node dissection rates were lower (41 vs. 45%, p < 0.0001). Among all patients, breast pCR was 49%, while nodal pCR was 64%. Compared with IHC2+/ISH+, IHC3+ had higher unadjusted breast (54 vs. 22%, p < 0.0001) and nodal (69 vs. 37%, p < 0.0001) pCR rates. When stratified by HR status, pCR was lower for HR+ disease but remained higher among IHC3+ patients. Analysis of T1cN0 primaries mirrored these trends. In multivariable analysis, IHC3+ remained an independent predictor of breast (odds ratio [OR] 3.91, confidence interval [CI] 3.65-4.19, p < 0.0001) and nodal (OR 3.40, CI 3.12-3.71, p < 0.0001) pCR. HER2 IHC status predicts pCR and may help select breast cancer patients who derive the greatest benefit from NT. These findings provide further evidence that revision of HER2 classification may improve clinical management.

Predicting nodal response to neoadjuvant treatment in breast cancer with core biopsy biomarkers of tumor microenvironment using data mining.

To generate a model for predicting nodal response to neoadjuvant systemic treatment (NAST) in biopsy-proven node-positive breast cancer patients (cN+) that incorporates tumor microenvironment (TME) characteristics and could be used for planning the axillary surgical staging procedure. Clinical and pathologic features were retrospectively collected for 437 patients. Core biopsy (CB) samples were reviewed for stromal content and tumor-infiltrating lymphocytes (TIL). Orange Datamining Toolbox was used for model generation and assessment. 151/437 (34.6%) patients achieved nodal pCR (ypN0). The following 5 variables were included in the prediction model: ER, Her-2, grade, stroma content and TILs. After stratified tenfold cross-validation, the logistic regression algorithm achieved and area under the ROC curve (AUC) of 0.86 and F1 score of 0.72. Nomogram was used for visualization. We developed a clinical tool to predict nodal pCR for cN+ patients after NAST that includes biomarkers of TME and achieves an AUC of 0.86 after tenfold cross-validation.

Albumin-To-Alkaline Phosphatase Ratio as a New Early Predictive Marker of Axillary Response in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy: A Pilot Study

Background and Objectives: The Albumin-to-Alkaline Phosphatase ratio (AAPR) is an easily applicable and cost-effective marker investigated as an outcome predictor in solid cancers. Preliminary evidence in breast cancer suggests that a low AAPR correlates with a poor response to neoadjuvant chemotherapy (NAC) in primary tumors. However, data regarding the axillary response are lacking. This study aims to evaluate whether the AAPR can predict the axillary response in initially nodal-positive (cN+) breast cancer patients undergoing NAC. Materials and Methods: Clinical and biochemical variables of cN+ breast cancer patients undergoing NAC were collected. Pre-NAC albumin and alkaline phosphatase serum values were utilized in the AAPR calculation. Fisher’s exact test was performed to identify differences between the two groups of patients (high and low AAPR according to the cut-off reported in the literature). The primary outcome was the nodal pathologic complete response (pCR) rate in the two groups of patients. Results: Nodal pCR was achieved in 20/45 (44.4%) patients. A total of 36/45 (80%) patients had an AAPR &gt; 0.583. Among patient and tumor characteristics, the only statistically significant difference between the two groups was the axillary pCR between the low and high AAPR groups (p-value = 0.03, OR = 0.129, 95% CI = 0.00–0.835). Conclusions: This pilot study suggests that the pre-treatment AAPR might be an early predictor of axillary response in cN+ breast cancer patients undergoing NAC. This result justifies further investigation in larger prospective trials to validate this finding.

SP6.2 - Oncological outcomes following sentinel lymph node biopsy in patients with node positive breast cancer at diagnosis who achieve an axillary pathological complete response to neoadjuvant systemic therapy

Abstract De-escalation of axillary surgery following neoadjuvant chemotherapy (NACT) for patients with node positive breast cancer at diagnosis have focused on ensuring a low false negative rate for those who undergo sentinel lymph node biopsy (SLN) only with limited data to date on oncological outcomes. This study aimed to assess the medium-term oncological outcome in patients who have an axillary pCR following NACT and undergo de-escalation of axillary surgery with only a SLN performed post NACT. A consecutive series of patients with cytologically proven node-positive breast cancer who received NACT and achieved a nodal pCR on SLN between 2013-2021 were retrospectively analysed. Eligible patients underwent an end of treatment axillary ultrasound and if axillary nodes appeared sonographically normal a sentinel node biopsy was performed, with dual modality mapping (radioisotope and blue dye) at the time of breast surgery. The primary outcome of interest was disease free recurrence (DFS), and the secondary outcome was isolated axillary recurrence. 79 patients (median age 48 years) received NACT and had cytologically proven node-positive disease at diagnosis and attained an axillary pathological complete response (pCR) post NACT. The median nodal yield at SLN was 4 (range 1-9). Median follow up was 4.4 years. Only 1 patient experienced an axillary recurrence. Triple negative subtype had the lowest overall DFS. In this cohort, axillary recurrence remains uncommon. The optimal surgical strategy for safe de-escalation of axillary surgery post NACT remains in focus with adjuncts such as nodal marking and targeted axillary currently under study.

Nodal Response and Survival After Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive Breast Cancer: 20-Year Experience from a Single Institution.

Axillary response to neoadjuvant endocrine therapy (NET) for the treatment of hormone receptor-positive breast cancer (HR+ BC) is not well-described. This study was designed to characterize nodal response after NET. Patients receiving NET followed by curative intent surgery at a comprehensive cancer center from 1998 to 2022 in a prospectively collected registry were included. Patients with distant metastasis were excluded. Primary outcome was nodal pathologic complete response (pCR). Downstaging was defined as post-NET decrease in category. We included 123 patients; the majority were cT2 (n = 59) or cT3 (n = 35), and cN0 (n = 81). Median age was 70.0 years (interquartile range 62.1-76.0). Forty-two patients (34.1%) were clinically node-positive. After NET, 73 (59.8%) underwent breast-conserving surgery. All patients underwent sentinel lymph node biopsy, and 12 (9.8%) underwent completion axillary lymph node dissection. In-breast downstaging was achieved in 51 (41.5%) patients, 1 (0.8%) had breast pCR, and 14 (11.4%) had breast upstaging. Axillary downstaging was achieved in 10 (23.8%), 6 patients (14.3%) had nodal pCR, and 14 (33.3%) had axillary upstaging. At 10-year follow-up, local recurrence was 1% and distant recurrence was 14%, while disease-free survival was 82%. After adjusting for demographic and clinical factors, age was the only characteristic associated with mortality (hazard ratio 1.07, 95% confidence interval 1.01-1.13). In HR+ BC treated with NET, long-term disease-free survival is good, although nodal pCR is uncommon for cN+ patients. Future studies are needed to elucidate optimal neoadjuvant systemic therapy and to delineate oncologically safe strategies to deescalate axillary management for residual microscopic disease.

Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers

BRCA1 and BRCA2 pathogenic variant carriers develop breast cancers with distinct pathological characteristics and mutational signatures that may result in differential response to chemotherapy. We compared rates of pathologic complete response (pCR) after NAC between BRCA1/2 variant carriers and noncarriers in a cohort of 1426 women (92 [6.5%] BRCA1 and 73 [5.1%] BRCA2) with clinical stage I–III breast cancer treated with NAC followed by surgery from 11/2013 to 01/2022 at Memorial Sloan Kettering Cancer Center. The majority received doxorubicin/cyclophosphamide/paclitaxel therapy (93%); BRCA1/2 carriers were more likely to receive carboplatin (p < 0.001). Overall, pCR was achieved in 42% of BRCA1 carriers, 21% of BRCA2 carriers, and 26% of noncarriers (p = 0.001). Among clinically node-positive (cN+) patients, nodal pCR was more frequent in BRCA1/2 carriers compared to noncarriers (53/96 [55%] vs. 371/856 [43%], p = 0.015). This difference was seen in HR+/HER2− (36% vs. 20% of noncarriers; p = 0.027) and TN subtypes (79% vs. 45% of noncarriers; p < 0.001). In a multivariable analysis of the overall cohort, BRCA1 status, and TN and HER2+ subtypes were independently associated with pCR. These data indicate that BRCA1 carriers may be more likely to achieve overall and nodal pCR in response to NAC compared with BRCA2 carriers and patients with sporadic disease. Further studies with a larger cohort of BRCA1/2 mutation carriers are needed, as a small sample size may have a restricted ability to detect a significant association between mutational status and pCR in sensitivity analyses stratified by subtype and adjusted for clinically relevant factors.

Abstract PO2-23-03: Potential Candidates for Conservative Axillary Surgery after Neoadjuvant Chemotherapy

Abstract BACKGROUND Neoadjuvant chemotherapy (NAC) plays a crucial role in breast cancer treatment. Besides having prognostic relevance, this downstaging allows for more conservative breast surgery, now the standard of practice. This strategy of de-escalation in axillary surgery after NAC is less stablished, especially in cN+ that turn into ycN0 tumors, where axillary lymph node dissection (ALND) or targeted ALND (TAD) with previous referencing of metastatic lymph combined with sentinel lymph node biopsy (SLNB) are options. Assuming that nodal complete pathologic response (pCR) after NAC is dependent of tumor biology, we intent to identify molecular subtypes or biological factors associated with nodal pCR, and so identify which ones are the potential candidates for a more conservative axillary approach, such as SLNB. METHODS From 1st January of 2017 to 31st December of 2021, all patients with cN+, ypN+(sn) and cT4Nx invasive breast cancer, who were submitted to ALND after NAC at our center, were retrospectively evaluated. Nodal pCR defined by absence of axillary invasive disease. RESULTS 591 patients were submitted to ALND after NAC during this 5-year period. Clinicopathological characteristics are described in table 1. Overall nodal pCR rate was 39.8%. The greatest nodal pCR rate occurred in the Her2 type (66.2%), following luminal B Her2+ (56.4%), TN (54%) and at least luminal B Her2- (27.2%) and luminal A (20.5%) tumors - p &amp;lt; 0.001. On univariate analysis, the subtypes Her2type (OR 3.400, 95%CI 1.974-5.855, p&amp;lt; 0.001), luminal BHer2+ (OR 2.237, 95%CI 1.431-3.497, p&amp;lt; 0.001) and TN (OR 2.011, 95%CI 1.303-3.103, p 0.002) are all associated with higher rates of nodal pCR. On the other hand, luminal A (OR 0.346, 95%CI 0.195-0.617, p&amp;lt; 0.001) and luminal B Her2- subtypes (OR 0.384, 95%CI 0.271-0.545, p&amp;lt; 0.001) are associated with less nodal pCR. Ki67 (OR 1.027, 95%CI 1.020-1.035, p&amp;lt; 0.001) and tumoral pCR (OR 13.688, 95%CI 8.693-21.552, p&amp;lt; 0.001) are also associated with higher rates of nodal pCR. On multivariate analysis, the subtypes Her2type and Luminal B Her2+ remain independently associated with nodal pCR – OR 2.417, 95%CI 1.078-5.549, p 0.032 and OR 2.080, 95%CI 1.005-4.304, p 0.049, respectively – as well as Ki67% (OR 1.019, 95%CI 1.009-1.030, p&amp;lt; 0.001) and tumoral pCR (OR 9.425, 95%CI 5.750-15.449, p&amp;lt; 0.001). When considering Ki67, TN tumors with Ki67≥50% are also identified as an independently associated factor with pCR – OR 4.946, 95%CI 1.190-20.559, p 0.028. DISCUSSION AND CONCLUSION The overall nodal pCR after NAC is around 40% and it clearly differs between molecular subtypes, being superior in the Her2type (66.2%), luminal B Her2+ (56.4%) and TN (54%) and at least 2 times inferior in luminal A (20.5%) and B Her2- tumors (27.2%). Data reveal Her2 expression (Her2type and luminal B Her2+) as an independent factor associated with higher nodal pCR rates, as well as the Ki67% and the tumoral pCR, consistent with tumor biology. In this series, the remaining molecular subtypes do not correlate in a consistent way with nodal pCR, but there’s a trend for luminal A and B Her2- to influence it negatively, as opposed to TN, which appears to influence it positively. Besides that, the subgroup of TN tumors with high proliferative rates (Ki67≥50%,) appears to correlate with nodal pCR on multivariate analysis. Parallel to tumoral pCR, nodal pCR can represent a chance to make axillary surgery more conservative. ALDN has a relevant morbidity and TAD, although less aggressive, requires a series of technical procedures that are usually difficult to perform in hospital facilities due to logistic constraints. Recognizing the subtypes which have more consistent nodal pCR, the so-called “good responders”, can help to identify which ones are the potential candidates for a more conservative approach, as is SLNB. In this study, Her2+ tumors and eventually TN with high Ki67, appear as those with greater consistency in nodal pCR, being possible targets for this strategy. Potential Candidates for Conservative Axillary Surgery after Neoadjuvant Chemotherapy Table 1 - Clinicopathological characteristics Citation Format: Beatriz Pereira Gonçalves, Beatriz Costeira, Cátia Fernandes da Cunha, Rodrigo Oom, Cristina Costa, João Vargas Moniz, Nuno Abecasis, Catarina Rodrigues dos Santos. Potential Candidates for Conservative Axillary Surgery after Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-03.

Abstract PO5-26-04: The value of skin involvement in achieving of pCR in patients with locally advanced breast cancer

Abstract Objective: The management of patients with locally advanced breast cancer (LABC) with skin involvement (edema or thickening) continues to be one of the most controversial topics in mammology. The most recommended conventional treatment strategies include systemic therapy (chemotherapy/hormone therapy/biological agents) followed by local therapy (surgery and/or radiation therapy). However, approximately 1/3 of patients with locally advanced breast cancer are “resistant” to neoadjuvant chemotherapy (which is manifested by the persistence of skin involvement/edema/thickening). In this study, we aimed to identify the relationship between skin involvement and clinicopathological features of LABC patients. In particular, we sought to develop the algorithm for skin involvement measurement and examine the impact of skin involvement on the rate of pCR. Materials and methods: We performed a retrospective analysis of 182 patients diagnosed with LABC from 2010 to 2018 at N.N. Blokhin National Cancer Research Center. All patients were treated with neoadjuvant hormone- or chemotherapy and were considered as borderline for surgical resection because of partial skin edema. Ninety one women received surgery with consecutive radiotherapy (first group) and 50 women (second group) received radiotherapy (total dose 50 Gy) with consecutive surgery after systemic treatment. We developed the algorithm for skin involvement measurement, using a series of formulas. We further interrogated the impact of skin involvement on the rate of breast and lymph node pathological response in every group. Results: The median percentage of skin edema before systemic therapy was 76.3% in the first group and 70.1% in the second group. The median percentage of skin edema after systemic therapy was 62.3% in the first group and 69.1% in the second group. There wasn`t a statistically significant difference between the two groups (р=0,675 and р = 0,286, respectively). Breast pCR was seen in 19,7% (n=18) of the first group patients and partial response was seen in 72.6% (n=66). Breast pCR was seen in 30% (n=15) of the second group patients and partial response was seen in 70% (n=35). Results showed no significant differences between groups, р=0,342 and р = 0,12, respectively. Nodal pCR was reported in 23,9% (n=16) and partial response in 50,8% (n=34) of the 67 node-positive patients. Nodal pCR was reported in 31,6% (n=12) and partial response in 65,8% (n=29) of the 38 node-positive patients of the second group. There was no statistical difference in the groups, p &amp;gt;0,05. Conclusion: Increasing attention has been paid to LABC patients due to the clinical commonness and the complexity of treatment. Our study showed that LABC patients with incomplete clinical response to neoadjuvant systemic therapy can achieve pCR or partial response of tumor despite partial skin edema. In this study we developed the algorithm for skin involvement measurement. We hope that knowledge about volume of skin involvement revealed by this study might shed light on individualized therapies for these patients. In future, it allows to evaluate criteria of tumor resectability to improve patient selection. Therefore, prospective randomized trials are needed to improve optimization of the local treatment. Citation Format: Viktory Amosova, Alexander Petrovskiy, Oxana Trofimova, Mona Frolova, Alexey Rumyantsev. The value of skin involvement in achieving of pCR in patients with locally advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-26-04.

Abstract PS01-02: Long-term outcomes of sentinel lymph node biopsy following neoadjuvant chemotherapy for initially node-positive breast cancer: A systematic review and meta-analysis

Abstract Background: Sentinel lymph node biopsy (SLNB) alone is now frequently offered to women with initially node-positive breast cancer who convert to pathologically node negative (nodal pCR) following neoadjuvant chemotherapy (NAC), despite limited long-term data regarding the oncologic safety of this approach. The aim of this meta-analysis was to evaluate the long-term oncologic outcomes associated with SLNB alone following NAC for initially node-positive breast cancer. Methods: A systematic review and meta-analysis was conducted according to PRISMA guidelines. Medline (Ovid), Embase, and Cochrane Central Registry were systematically searched for studies comparing women undergoing SLNB or ALND following NAC for initially clinically node-positive breast cancer. Included studies reported one of the following outcomes: axillary recurrence (AR), locoregional recurrence (LRR), disease-free survival (DFS) or overall survival. A random effects meta-analysis was used to calculate weighted pooled effect estimates (risk ratios, RR) for all outcomes. Variability across studies due to heterogeneity was estimated using I2 statistics. Subgroup analysis was performed by length of follow-up for each study. Risk of bias within studies was assessed using the Newcastle-Ottawa Scale (NOS). Results: Data for participants undergoing treatment between 2004 and 2022 was captured across studies. The median age of women treated with NAC for initially node-positive breast cancer ranged from 46 to 60 years. The median follow-up time ranged from 19.5 to 108 months across included studies. Nine observational studies were eligible for meta-analysis. No studies were excluded from the analysis on the basis of quality: Newcastle-Ottawa Scale scores ranged from 6 to 9 (maximum possible score of 9). Rates of axillary recurrence (AR) were low across all included studies (range 0.0% to 5.6%). For AR, data for 2,882 patients from 7 studies was quantitatively synthesized (SLNB=1,964; ALND=917). For LRR, data for 2,629 patients from 7 studies was quantitatively synthesized (SLNB=1,857; ALND=771). No significant differences were observed in AR between patients undergoing SLNB alone versus ALND following NAC for initially node-positive breast cancer: pooled RR 1.02 (95% CI: 0.46-2.29, I2=0.0%). Similarly, no significant differences were observed in LRR (RR 0.70, 95% CI: 0.45-1.10, I2=0.0%), DFS (RR 0.77, 95% CI: 0.55-1.08, I2=0.0%), nor overall mortality (RR 0.66, 95% CI: 0.33-1.33, I2=0.0%) between the SLNB and ALND groups. Conclusions: Among patients who convert to node-negative following NAC, this meta-analysis suggests that SLNB alone does not result in significantly different oncologic outcomes compared to ALND, and that de-escalation of axillary surgery to SLNB alone in this context may be safely considered in this patient population. Citation Format: Mariam Rana, Anna Weiss, Alison Laws, Carol Mita, Tari King. Long-term outcomes of sentinel lymph node biopsy following neoadjuvant chemotherapy for initially node-positive breast cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS01-02.

Abstract PS04-03: Survival benefit of regional nodal irradiation in clinically node-positive breast cancer following neoadjuvant chemotherapy and breast-conserving surgery

Abstract Introduction: In recent years, there has been increasing use of neoadjuvant chemotherapy (NAC) and pathologic complete response (pCR) rates for certain breast cancer phenotypes (40-70%). Although encouraging, this has resulted in uncertainties in traditional axillary management. Meanwhile, clinically node-positive (cN+) patients who have a low burden of disease downstaged to node-negative (ypN0) after NAC and get breast-conserving surgery (BCS) may avoid an axillary lymph node dissection (cALND) but still have regional nodal irradiation (RNI) recommended regardless of axillary surgery. Those who remain node-positive (ypN+) undergo cALND and RNI with an increased risk of lymphedema. In this study, we evaluated the survival benefit of RNI in cN+ patients after NAC and BCS. Methods: We reviewed (cN+) stage I-III non-inflammatory female breast cancer patients who underwent NAC followed by BCS between 2010 and 2020 in the National Cancer Database (NCDB). Patients having a history of another malignancy who received hormone therapy or radiotherapy before surgery or whose pathologic nodal status (ypN) was unknown were excluded. Overall survival (OS) from surgery was compared between those who did and did not receive RNI. Patient and tumor characteristics were compared across subgroups using chi-square and Wilcoxon rank sum tests. Weighted Kaplan-Meier curves and log-rank tests were used to assess the effect of RNI on OS. As a sensitivity analysis, analyses were stratified based on yPN status. Finally, multivariable logistic regression was used to determine predictors of receiving RNI. Results: The 8,250 cN+ patients had a mean age of 54.6±11.1 years. In total, 69.1% of patients were White, 23.9% were Black, and 10.2% were Hispanic. The mean number of removed and positive nodes were 10.0 ±7.8 and 2.3±3.8. The most common histology and phenotype were invasive ductal carcinoma (IDC) in 94.3% and hormone-positive (HR+) in 41.0%. Breast and nodal pCR rates were 25.9% and 34.7%, with nodal pCR achieved in 20.7%, 46.0%, and 44.4% of HR+, HER2+, and triple-negative tumors. RNI was performed in 52.1% of the patients (45.3% of the yPN0 and 55.9% of the yPN+). The mean number of nodes removed was 10.4±7.8 in the RNI+ and 9.6±7.7 in the RNI- groups (P &amp;lt; 0.01). The mean number of positive nodes was 2.6±4.0 in the RNI+ and 1.9±3.6 in the RNI- groups (P &amp;lt; 0.01). On multivariable analysis, the predictors of RNI administration included the number of positive nodes (p &amp;lt; 0.01), cN stage (p &amp;lt; 0.01), cT3 (p &amp;lt; 0.01), and tumor phenotype (p &amp;lt; 0.01). Grade I tumors (p=0.04) and Medicare beneficiaries (p=0.01) were less likely to get RNI. The survival rates were 79.9% and 81.9% in the RNI+ and RNI– groups, with a median follow-up of 62.1±31.4 and 62.8±32.2 in the RNI+ and RNI- groups. In the entire cohort, ypN0 patients had improved OS when compared with ypN+ patients (p &amp;lt; 0.001), but in adjusted analyses, there was no difference in OS between those who did and did not receive RNI (p=0.6). There was also no difference in OS comparing those who did and did not receive RNI in the ypN0 (p=0.96) or ypN+ (p=0.76) groups. Conclusion: For breast cancer patients having a modest nodal burden of disease and BCS after NAC, traditional prognostic factors such as stage and nodal status, as well as phenotype, grade, and the presence or absence of pCR, impact overall survival. Although some such factors appear to bias practitioners into giving RNI for patients undergoing NAC and BCS, RNI after NAC and BCS does not improve OS, regardless of pCR status, even at a mean follow-up time of 5.5 years. Further studies evaluating the impact on local control and longer-term outcomes should be pursued to enable the creation of specific guidelines surrounding indications for RNI based on the initial burden of disease and the final response from NAC administration. Citation Format: Mahtab Vasigh, Richard Bleicher, Austin Williams, Allison Aggon, Mary Pronovost, Andrea Porpiglia, Matthew Pierotti, Christian Cruz Pico. Survival benefit of regional nodal irradiation in clinically node-positive breast cancer following neoadjuvant chemotherapy and breast-conserving surgery [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-03.

Abstract PO5-18-10: Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104)

Abstract Background: Currently, axillary surgery for breast cancer is considered a staging procedure that does not seem to influence breast cancer mortality since the risk of developing metastasis depends mainly on the biological behavior of the primary (seed-and-soil model). Based on this, postsurgical therapy should be considered based on biological tumor characteristics. Retrospective data of cancer registry trials showed a strong correlation between breast pathologic complete response (pCR) and nodal pCR depending on intrinsic subtypes. Improvements in systemic treatments for breast cancer have increased the rates of pCR in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to decrease, and perhaps eliminate, surgery in patients who have a pCR. Trial design: The EUBREAST network designed a clinical trial (NCT04101851) in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included, and type of surgery will be defined according to the response to NAST rather than on the classical T and N status at presentation. In the ongoing trial, axillary surgery will be eliminated (no axillary sentinel lymph node biopsy [SLNB]) for initially clinical node-negative (cN0) patients with radiologic complete remission (rCR) and a breast pCR (ypT0/ypTis) as determined in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (N=440 as the screening population with an expected 80% pCR-rate) which might give practice-changing results in a short period, sparing the time and the costs of a randomized comparison. Patients will be recruited in European countries (Austria, Germany, Italy, and Spain) over 48 months. Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy). Multifocal or multicentric tumors are allowed if breast-conserving surgery (BCS) is planned. -Age at diagnosis at least 18 years -imaging techniques with estimated tumor stage between cT1-T3 before NAST -triple-negative (TNBC) or HER2-positive invasive breast cancer -TNBC is defined by: ER-negative (&amp;lt; 10% positive cells in IHC) and PgR-negative (&amp;lt; 10% positive cells in IHC), HER2-negative -clinically and sonographically tumor-free axilla before core biopsy (cN0/iN0) -in cases with cN0 and iN+, a negative core biopsy or fine-needle aspiration biopsy of the sonographically suspected lymph node is required -no evidence for distant metastasis (M0) -standard NAST with rCR -planned BCS with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Primary objective: 3-year rate of axillary recurrence-free survival (ARFS) after BCS Statistics: The calculated total case number for per-protocol analysis is N=350, and the expected total number of screened patients is N=440. The assumption for acceptable 3-year ARFS ≥98.5% in the experimental arm is based on previous study findings. Timelines: -First patient in: January 2021 -Last patient in: December 2024 -Primary outcome analysis: Q1/2027 Current accrual: In June 2023, 255 patients were recruited; the majority of them in Germany. Contact: Prof. Dr. Toralf Reimer (eubreast-01@kliniksued-rostock.de), study chair Dr. Oreste D. Gentilini (gentilini.oreste@hsr.it), study co-chair Funding by Else Kroener-Fresenius Foundation, German Society of Senology, University of Rostock (Germany), and San Raffaele Hospital (Milan, Italy). Citation Format: Toralf Reimer, Bernd Gerber, Thorsten Kuehn, Nikola Bangemann, Anke Kleine-Tebbe, Andrea Stefek, Ulrike Doerste, Carolin Hammerle, Oliver Hoffmann, Alexander Hein, Isabel Rubio, Florentia Peintinger, Keyur Mehta, Sibylle Loibl, Edoardo Botteri, Oreste Gentilini. Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-10.

Abstract PO3-01-12: Clinicopathologic Factors affecting response in patients with Estrogen receptor-positive and Human Epidermal Growth Factor Receptor-negative breast cancer receiving neoadjuvant chemotherapy

Abstract Background: The evolution of Neoadjuvant chemotherapy(NAC) regimen has enabled the down-staging of locally advanced breast cancer, allowing patients to undergo breast conserving surgery. NAC is known to be effective in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. However, the role of NAC in hormone receptor-positive and HER2-negative (HR+HER2-) breast cancer patients remains unclear. In this study, we aimed to explore the utility of NAC for estrogen receptor-positive and HER2-negative (ER+HER2-) breast cancer patients. Methods: Clinical data were collected from 120 patients who were diagnosed with estrogen receptor (ER)-positive and HER2-negative breast cancer and received neoadjuvant chemotherapy between July, 2017 and April, 2023 at Seoul St Mary’s Hospital (Seoul, Korea). We analyzed the factors that affect clinical response subgroups, including pathologic complete response (pCR), partial response (PR), stable disease(SD), and progressive disease (PD), following neoadjuvant chemotherapy. The median follow-up period was 17 months. &amp;lt; Results: Among 120 patients after NAC, 5.8% achieved pCR, while 67.5% had a partial response. The median age at the time of surgery was 55 years at pCR group, 49 years at PR group, 47 years at SD group, and 49 years at PD group. Although the age of patients achieving pathological complete response was higher, this differences was not statistically significant. Patients achieving pCR had a higher incidence of progesterone receptor (PR) negativity (pCR 71.4% vs PR 30.9%, p=0.011) and higher levels of Ki-67 expression than those who did not achieve pCR (71.7% vs 35.6%, p=0.003). Also, there was no significant difference in Androgen receptor (AR) and HER-2 expression between the groups. Tumor size was also significantly associated with clinical response (p=0.003). However, no differences in clinical response was observed between patients with lymph node metastasis (p=0.221). Our analysis of 107 patients who were clinically N positive before NAC showed that the Ki-67 index level was the only factor found to affect nodal pCR. In addition, in the non-pCR group, patients with a Ki-67 index of less than 20% after neoadjuvant had a significantly better disease-free survival (5yr DFS, 79.8% vs 65.9%, p=0.039) Conclusion: Our analysis revealed that patients with higher levels of Ki-67 and lower level of PR expression were more likely to achieve pCR or PR. Also, decrease in Ki-67 index was confirmed to be an important prognostic factor of ER+ HER2- breast cancer. A combination of clinical and molecular factors, such as tumor size, progesterone receptor expression, and Ki-67 expression, can be used to optimize treatment plans and improve outcomes for the patient population. Citation Format: Jin Ah Lee, Young Joo Lee, Dooreh Kim, Chang Ik Yoon, Woo-Chan Park, Soo Youn Bae. Clinicopathologic Factors affecting response in patients with Estrogen receptor-positive and Human Epidermal Growth Factor Receptor-negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-12.

Abstract PO1-23-01: A novel nomogram for predicting the possibility of omitting axillary lymph node dissection after neoadjuvant chemotherapy for clinical node-positive breast cancer

Abstract Purpose: Currently, there is no validated strategy established for omitting axillary lymph node dissection (ALND), when axillary node metastases are expected to disappear with neoadjuvant chemotherapy (NAC) for clinical node-positive (cN+) breast cancers. In contrast, it was reported that the axillary pathological complete response (pCR) rate to NAC for cN+ breast cancer is approximately 40%. Therefore, it is necessary to develop a more accurate method for predicting nodal pCR (ypN0) to select patients who can omit ALND after NAC for cN+ breast cancer. Methods: This is a single-centered, retrospective clinical study conducted in 128 patients with cN+ primary breast cancer who underwent ALND after NAC between January 2014 and July 2021 at Saitama Medical Center. Clinical complete response (cCR) was defined as the disappearance of the primary tumor or axillary node metastasis, as confirmed by the findings of imaging. The pCR was defined as the absence of microscopic evidence of residual invasive carcinoma in primary breast tumor or axillary nodes. Clinicopathological variables were compared using Fisher’s exact test or logistic regression, as appropriate. Statistical significance was set at p&amp;lt; 0.05. Results: The median age of the patients was 52 years; 48.4% were premenopausal, 38.3% had cT3 or higher, 22.7% had cN2 or higher, and 50% had stage III disease. Estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) positivity accounted for the patients were 58.6%, 50%, and 31.3%, respectively. NAC included sequential taxanes and anthracyclines in 47.7% of the patients, and anti-HER2 therapy was used in all patients of HER2-positive breast cancer. Breast primary tumor cCR (ypT0) was 29.7% and ypN0 was 44.5%. The ypN0 rate was 19.5% higher than the ypT0 rate in all patients (p &amp;lt; 0.001); it was 4.8% higher in the luminal subtype (p=0.009), 25.5% higher in the triple-negative subtype (p &amp;lt; 0.001), and 29.3% higher in the HER2 subtype (p=0.015). Additionally, the ypN0 rate was 3.9% higher than the axillary node cCR (ycN0) rate in all patients (p &amp;lt; 0.001), 7.6% lower in luminal type (p &amp;lt; 0.001), 13.6% higher in triple-negative type (p &amp;lt; 0.001), and 5% higher in the HER2 subtype (p=0.006). When ycN0 was predicted to be ypN0, the negative predictive value (NPV) was 77.2% and the false negative rate (FNR) was 19.7% (Table 1). In the association between ypN0 and preoperative clinico-pathological factors in cN+ breast cancer treated with NAC, univariate analysis showed significant differences in ER negativity (ER-) [hazard ratio (HR): 0.186, 95% confidence interval (CI): 0.086–0.401, p&amp;lt; 0.001], PgR negativity (HR: 0.360, 95% CI: 0.176–0.736, p=0.005), HER2 positivity (HER2+) (HR: 4.394, 95% CI: 1.941–9.949, p&amp;lt; 0.001), ycT0 (HR: 10.667, 95% CI: 4.020–28.304, p&amp;lt; 0.001), and ycN0 (HR: 9.966, 95% CI: 4.399–922.576, p&amp;lt; 0.001). The multivariate analysis revealed that ER, ycT0, and ycN0 were independent predictive factors for ypN0 after NAC in the patients with cN+ breast cancer (Table 2). These independent factors in multivariate analysis were used to create a nomogram for ypN0 prediction. The points added were 82 if the patient was ER-, 56 if the patient was ycT0, and 100 if the patient was ycN0, and the total of these scores was used to predict whether the patient had ypN0. When the Receiver Operating Characteristic curve was used to determine the cut-off value of the total points, 119 or more points were predicted to be ypN0, the NPV was 92.9%, and the FNR was 4.5%, which demonstrated an approximately 15% improvement over the prediction of ypN0 by ycN0 alone (Table 3). Conclusion: ER, ycT0, and ycN0 are independent predictive factors of ypN0 in cN+ breast cancer, suggesting that ypN0 prediction using a nomogram may contribute to individualized axillary treatment. Table 1. Accuracy of ypN0 prediction with ycN0 after NAC for clinical node-positive breast cancer Table2. Univariate and multivariate analyses of the relationship between preoperative clinicopathological factors and pathologically axillary node-negative after neoadjuvant chemotherapy in clinical node-positive breast cancer Table 3. Accuracy of ypN0 prediction after NAC for clinical node-positive breast cancer using Nomogram Citation Format: Hirohito Seki, Yuki Ishiguro, Ken Shimizu, Akitsugu Makino, Yoshiharu Ishizaka, Ai Tsuchiya, Hirotsugu Isaka, Shigeru Imoto. A novel nomogram for predicting the possibility of omitting axillary lymph node dissection after neoadjuvant chemotherapy for clinical node-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-23-01.

The Impact of Neoadjuvant Chemotherapy on Axillary Surgical Management of Patients With Breast Cancer and Positive Axillary Lymph Nodes.

Sentinel lymph node biopsy (SLNB) is effective in patients with breast cancer (BC) and positive axillary lymph nodes undergoing neoadjuvant chemotherapy (NAC). However, the frequency with which axillary lymphadenectomy (ALND) can be avoided remains debated. This study aimed to identify patient populations that can benefit from this approach. The data of 195 consecutive patients with BC and positive axillary lymph nodes at diagnosis who underwent NAC were retrospectively analyzed. In all cases, the positivity of the lymph nodes was confirmed by cytological examination. Patients converted to ycN0 after NAC were considered eligible for SLNB. Indications for ALND were failed mapping, fewer than three SLNs recovered, and positive SLNs. Of 195 cN1 patients potentially eligible for SLNB, 71 (36.4%) remained clinically ycN+ after NAC and underwent elective ALND, while 124 (83.7%) converted to ycN0 after NAC and SLNB. The lymph node identification rate was 95.9% (119/124 patients) with three or more SLNs recovered in 83 cases (89.8%). One or two lymph nodes were recovered in 36 cases (30.2%). Nodal pathologic complete response (pCR) was found in 34/83 (40.9%) patients with three or more SLNs recovered. Considering all 195 patients initially included in the study, 55 patients (28.2%) achieved lymph node pCR after NAC. Nodal pCR varied based on hormone receptor and HER2 status, with rates ranging from 20.7% for ER+/HER2- patients to 95.3% for ER-/HER2+ patients (p<0.001). More than 80% of cN1 patients in our study were eligible for SLNB after NAC. ALND could be avoided in approximately 30% of cases, supporting the role of NAC in reducing the need for ALND among patients with lymph node metastases.

Axillary Surgery for Breast Cancer in 2024.

Axillary surgery for patients with breast cancer (BC) in 2024 is becoming increasingly specific, moving away from the previous 'one size fits all' radical approach. The goal is to spare morbidity whilst maintaining oncologic safety. In the upfront surgery setting, a first landmark randomized controlled trial (RCT) on the omission of any surgical axillary staging in patients with unremarkable clinical examination and axillary ultrasound showed non-inferiority to sentinel lymph node (SLN) biopsy (SLNB). The study population consisted of 87.8% postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative BC. Patients with clinically node-negative breast cancer and up to two positive SLNs can safely be spared axillary dissection (ALND) even in the context of mastectomy or extranodal extension. In patients enrolled in the TAXIS trial, adjuvant systemic treatment was shown to be similar with or without ALND despite the loss of staging information. After neoadjuvant chemotherapy (NACT), targeted lymph node removal with or without SLNB showed a lower false-negative rate to determine nodal pathological complete response (pCR) compared to SLNB alone. However, oncologic outcomes do not appear to differ in patients with nodal pCR determined by either one of the two concepts, according to a recently published global, retrospective, real-world study. Real-world studies generally have a lower level of evidence than RCTs, but they are feasible quickly and with a large sample size. Another global real-world study provides evidence that even patients with residual isolated tumor cells can be safely spared from ALND. In general, few indications for ALND remain. Three randomized controlled trials are ongoing for patients with clinically node-positive BC in the upfront surgery setting and residual disease after NACT. Pending the results of these trials, ALND remains indicated in these patients.

Nomogram Based on US and Clinicopathologic Characteristics: Axillary Nodal Evaluation Following Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer

BackgroundTo develop a convenient modality to predict axillary response to neoadjuvant chemotherapy (NAC) in breast cancer patients. Materials and MethodsIn this multi-center study, a total of 1019 breast cancer patients with biopsy-proven positive lymph node (LN) receiving NAC were randomly assigned to the training and validation groups at a ratio of 7:3. Clinicopathologic and ultrasound (US) characteristics of both primary tumors and LNs were used to develop corresponding prediction models, and a nomogram integrating clinicopathologic and US predictors was generated to predict the axillary response to NAC. ResultsAxillary pathological complete response (pCR) was achieved in 47.79% of the patients. The expression of estrogen receptor, human epidermal growth factor receptor -2, Ki-67 score, and clinical nodal stage were independent predictors for nodal response to NAC. Location and radiological response of primary tumors, cortical thickness and shape of LNs on US were also significantly associated with nodal pCR. In the validation cohort, the discrimination of US model (area under the curve [AUC], 0.76) was superior to clinicopathologic model (AUC, 0.68); the combined model (AUC, 0.85) demonstrates strong discriminatory power in predicting nodal pCR. Calibration curves of the nomogram based on the combined model demonstrated that substantial agreement can be observed between the predictions and observations. This nomogram showed a false-negative rates of 16.67% in all patients and 10.53% in patients with triple negative breast cancer. ConclusionNomogram incorporating routine clinicopathologic and US characteristics can predict nodal pCR and represents a tool to aid in treatment decisions for the axilla after NAC in breast cancer patients.

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

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. 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. 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%. 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.

89Zr-Trastuzumab PET/CT Imaging of HER2-Positive Breast Cancer for Predicting Pathological Complete Response after Neoadjuvant Systemic Therapy: A Feasibility Study.

Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of -48% and -90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was -79% and -94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer.

Postmastectomy Radiation in HER-2 Positive Breast Cancer after Neoadjuvant Therapy: Secondary Analysis of Two Randomized Trials

The role of postmastectomy radiation therapy (PMRT) following primary systemic therapy (PST) in HER-2 positive breast cancer (Her2+BC) remains poorly understood. The current study evaluates PMRT based on the pathological response to PST in Her2+BC. TRYPHAENA and NeoSphere are randomized phase II trials that investigated PST for Her2+BC. Our study is a pooled analysis of both trials, including 312 node-positive patients treated with HER-2 targeted PST followed by mastectomy with or without PMRT. The primary endpoint is loco-regional recurrence-free survival (LRRFS). Our analysis included 172 (55%) patients who achieved nodal pCR and 140 (45%) patients who did not. Patients with nodal pCR had a 5-year LRRFS of 97% with PMRT delivered in 98 patients (57%). Patients without nodal pCR had a 5-year LRRFS of 87% with PMRT delivered in 93 patients (66%). Patients with ypN1 (n = 62) disease who received PMRT (n = 40) had a 5-year LRRFS of 85% as compared to 89% in those who did not (n = 22); (p = 0.60). A significant LRRFS difference was noted in patients with ypN2-3 (n = 78) disease who received PMRT (n = 53) compared to those who did not (n = 25) (5-year LRRFS 92% vs. 75%; p = 0.019). On multivariate analysis, clinical nodal disease at diagnosis and nodal pCR were significantly associated with loco-regional recurrence (LRR). Her2+BC patients who achieve nodal pCR after PST have excellent loco-regional control which supports de-escalation of PMRT.

Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers.

544 Background: Distinct pathological characteristics and mutational signatures in BRCA-associated breast cancers may result in differential response to chemotherapy but understanding of treatment response after neoadjuvant chemotherapy (NAC) is limited. We describe a single-institutional experience to compare rates of pathologic complete response (pCR) after NAC in BRCA carriers (g BRCA1/2) and noncarriers. Methods: From 11/2013 to 01/2022, 1426 consecutive women with clinical stage I-III breast cancer were treated with NAC followed by surgery. Baseline disease characteristics were compared between g BRCA1/2 and noncarriers using two-sample non-parametric tests. Conditional logistic regression was used to evaluate the association between BRCA status and pCR (i.e., ypT0/is pN0) adjusting for variables selected using backward elimination. Results: 92 (6.5%) and 73 (5.1%) had deleterious mutations in BRCA1 and BRCA2, respectively. Compared to noncarriers, g BRCA1/2 were younger (p&lt;0.001) with clinical T1 (p=0.002) and triple negative disease (TN) (57% vs 25% noncarriers, p&lt;0.001). Almost all patients received doxorubicin/cyclophosphamide/paclitaxel therapy (93%) with g BRCA1/2 more likely to receive carboplatin (p&lt;0.001). pCR rate was 42% of g BRCA1, 21% of g BRCA2, and 26% of noncarriers (p=0.001). Among clinically node positive (cN+) patients, nodal pCR was higher in g BRCA1/2 compared to noncarriers (53/96 (55%) vs 371/856 (43%), p=0.012). This difference was seen in ER+/HER2- (36% gBRCA1/2 vs 20% noncarriers; p=0.027) and TN subtypes (79% g BRCA1/2 vs 45% noncarriers; p&lt;0.001). Poorly differentiated tumors (p&lt;0.001), cN+ (p=0.010), lower cT stage (p=0.028), ductal histology (p&lt;0.001), TN and HER2+ receptor status (p&lt;0.001), absence of lymphovascular invasion (p&lt;0.001), carboplatin receipt (p=0.041), and BRCA1 status (p=0.001) were also associated with pCR on univariate analysis. After adjusting for differentiation and molecular subtype, BRCA1 status remained independently associated with pCR. Conclusions: g BRCA1 undergoing NAC have higher pCR rates relative to g BRCA2 and patients with sporadic disease. Across breast cancer subtypes, g BRCA1/2 more frequently converted to pN0. Defining biological mechanism for these findings would allow customization of treatment based on germline genetics. [Table: see text]