Neoadjuvant systemic therapy for breast cancer: the Westmead experience.

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 36 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 (< 10% positive cells in IHC) and PgR-negative (< 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 2023 -Primary outcome analysis: Q1/2027 Current accrual: In June 2022, 150 patients were recruited in Germany and Italy. 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, Thorsten Kuehn, Angrit Stachs, Anke Kleine-Tebbe, Nikola Bangemann, Andrea Stefek, Carolin Hammerle, Jörg Heil, Antje Nixdorf, Gabriele Bonatz, Agnieszka Nolte, Isabel T. Rubio, Florentia Peintinger, Keyur Mehta, Sibylle Loibl, Edoardo Botteri, Oreste Davide 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 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-07-01.

Background: Pathological complete response (pCR) after neoadjuvant systemic treatment represents a good surrogate marker for the prognosis of Her-2 positive Breast Cancer (BCs). The results improved after adding anti-Her-2 therapy to chemotherapy in neoadjuvant setting. Methods: Our retrospective study enrolled a cohort of 56 invasive Her-2 positive non-metastatic BCs treated with neoadjuvant systemic therapy between 2001 and 2018. The patients received neoadjuvant chemotherapy with or without anti-Her-2 therapies before surgery and adjuvant endocrine and anti-Her-2 treatment together with adjuvant radiotherapy, based on clinical, pathological and hormonal receptor expression characteristics. The primary end point was pCR rate and disease-free-survival (DFS), defined as the interval between surgery and documented disease recurrence, progression, or death from any cause. Results: The rate of pCR for our patients was 41% independent of type of chemotherapy regimen and the anti-Her-2 therapy used. The results were improved by adding Trastuzumab in the neoadjuvant setting with statistical significance (p = 0.038). Median DFS was 68 months for the entire cohort. The risk of recurrence was higher in the group without pCR after neoadjuvant treatment (52% vs 17%; p = 0.003). 10 patients died (18%), all of them from group without pCR. The prognosis at 36-months was good, with 84% survival chance at 3 years follow-up. Conclusion: Our retrospective study underlines the positive impact of neoadjuvant systemic treatment on pCR rate and on disease-free survival in real-life Her-2 positive breast cancer patients.

Background: Pathological complete response (pCR) after neoadjuvant systemic treatment represents a good surrogate marker for the prognosis of Her-2 positive Breast Cancer (BCs). The results improved after adding anti-Her-2 therapy to chemotherapy in neoadjuvant setting. Methods: Our retrospective study enrolled a cohort of 56 invasive Her-2 positive non-metastatic BCs treated with neoadjuvant systemic therapy between 2001 and 2018. The patients received neoadjuvant chemotherapy with or without anti-Her-2 therapies before surgery and adjuvant endocrine and anti-Her-2 treatment together with adjuvant radiotherapy, based on clinical, pathological and hormonal receptor expression characteristics. The primary end point was pCR rate and disease-free-survival (DFS), defined as the interval between surgery and documented disease recurrence, progression, or death from any cause. Results: The rate of pCR for our patients was 41% independent of type of chemotherapy regimen and the anti-Her-2 therapy used. The results were improved by adding Trastuzumab in the neoadjuvant setting with statistical significance (p = 0.038). Median DFS was 68 months for the entire cohort. The risk of recurrence was higher in the group without pCR after neoadjuvant treatment (52% vs 17%; p = 0.003). 10 patients died (18%), all of them from group without pCR. The prognosis at 36-months was good, with 84% survival chance at 3 years follow-up. Conclusion: Our retrospective study underlines the positive impact of neoadjuvant systemic treatment on pCR rate and on disease-free survival in real-life Her-2 positive breast cancer patients.

e18624 Background: Triple negative breast cancer (TNBC) & HER2 positive breast cancer (Her2BC), are aggressive breast cancer subtypes. Both are associated with higher mortality in Non-Hispanic Black (NHB) compared to Non-Hispanic White women (NHW). Factors attributed to this racial disparity include socioeconomic status, insurance status, diagnosis(dx)/ treatment delays & comorbidities. We examined the association between race & clinical outcomes (pathological complete response, pCR; recurrence free survival, RFS & overall survival, OS) in patients (pts) dxed with TNBC/Her2BC treated with neoadjuvant chemotherapy (NAC) at Roswell Park Comprehensive Cancer Center. Methods: Pts dxed with Stage I-III TNBC/Her2BC who received NAC from 2000-2018 were included. pCR was defined as absence of residual invasive cancer in the breast & lymph nodes after NAC. Association of race with pCR & survival outcomes was evaluated using logistic & Cox regression models, respectively. Multivariate (MV) models were used to evaluate the association between race & pCR or survival while controlling for relevant confounders including age, BMI, insurance, comorbidities, clinical stage, grade & time from dx to chemotherapy(chemo)/surgery. Analysis was conducted using SAS v9.4 at a significance level of 0.05. Results: 174 TNBC (49 NHB, 125 NHW) & 80 Her2BC (13 NHB, 67 NHW) pts were analyzed. Among TNBC pts, NHB pts had higher baseline BMI(34.3 vs 28.6 kg/m2; p<0.001), higher incidence of hypertension (HTN) (45% vs. 24%; p<0.01), diabetes mellitus (20% vs 8%; p<0.05) & higher Medicare/Medicaid use (M/M) (55% vs. 28%; p<0.01). Among Her2BC pts, NHB pts had higher incidence of HTN (54% vs 25%; p<0.05). There was no statistically significant difference in mean chemo relative dose intensity by race. Among TNBC pts, those with pCR were younger (47 vs 53 yrs; p=0.002) & had more grade 3 tumors (96% vs 80.5%; p<0.05) at dx compared to pts without pCR. Similarly, among Her2BC pts, those with pCR had more grade 3 tumors (64% vs 36%; p<0.05) at dx compared to pts without pCR. Among TNBC pts, advanced age, higher clinical stage & longer time from dx to surgery were associated with worse RFS & OS (p<0.05). Among Her2BC pts, M/M use & advanced clinical stage were associated with worse RFS & OS (p<0.05). There were no significant associations between race & pCR/RFS/OS on MV analysis (table below). Conclusions: Similar outcomes were noted between races for TNBC/Her2BC pts treated at a single academic center in Buffalo, NY. Given the known genetic diversity of African American ancestry in the US, further studies investigating the interplay between race, geography & clinical outcomes are warranted.[Table: see text]

Background. Achieving a pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) is a predictive factor for improving disease free and overall survival. In triple negative (TN) and HER2-positive breast cancer (BC), the pCR rate exceeds 60 %. Patients with TN and HER2-positive BC who demonstrate an excellent response to NST are like­ly ideal candidates for downsizing surgery. The condition for reducing the volume of surgical intervention is a reliable determination of pathologic complete response using instrumental imaging and biopsy methods.Aim. To further assess the accuracy of post-NST image-guided biopsy to predict pCR.Materials and methods. Sixty one patients with T1-3N0-3 triple negative or HER2-positive BC receiving NST in the Department of Breast Tumors of the NMRC of Oncology named after N.N. Petrov in the period from 2017 to 2019 were enrolled in this single-center retrospective trial. Patients underwent ultrasound-guided core-biopsy of the initial breast tumor region before surgery. Findings were compared with findings on pathologic evaluation of surgical specimens to determine the performance of biopsy in predicting pCR after NST.Results. After neoadjuvant systemic therapy, clinical partial response (cPR) was diagnosed in 47 (77 %) patients, clinical complete response (cCR) in 14 (23 %) patients. pCR in the core-biopsy tissue and surgical material was achieved in 46 (75.4 %) and 37 (60.7 %), respectively. Performance of image-guided core-biopsy: sensitivity 100 % (95 % confldence interval (CI) 90.51-100), specificity 62.5 % (95 % CI 40.59-81.20), false-negative rate (FNR) 0 %, positive-pre­dictive value (PPV) 75.00 % (95 % CI 59.46-85.99), negative predictive value (NPV) 100.00 %.Conclusion. This retrospective trial showed that ultrasound-guided core biopsies are accurate enough to identify breast pCR in patients with triple-negative or HER2-positive BC with good response after NST (FNR 0 %). Based on these results, a prospective clinical trial has commenced in which breast surgery is omitted in patients with a breast pCR after NST according to image-guided biopsy.

BackgroundAxillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT combined with pathological axillary treatment response has been proposed to guide de-escalation of axillary treatment for clinically node-positive breast cancer patients treated with neoadjuvant systemic therapy. The aim of this study was to assess whether axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT and breast cancer molecular subtype are predictors of axillary pCR.MethodsThis study included clinically node-positive patients treated with neoadjuvant systemic therapy in the prospective Radioactive Iodine Seed placement in the Axilla with Sentinel lymph node biopsy (‘RISAS’) trial (NCT02800317) with baseline [18F]fluorodeoxyglucose PET/CT imaging available. The predictive value of axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT and breast cancer molecular subtype to estimate axillary pCR was evaluated using logistic regression analysis. Discriminative ability is expressed using ORs with 95% confidence intervals.ResultsOverall, 185 patients were included, with an axillary pCR rate of 29.7%. The axillary pCR rate for patients with limited versus advanced baseline axillary disease according to [18F]fluorodeoxyglucose PET/CT was 31.9% versus 26.1% respectively. Axillary disease extent was not a significant predictor of axillary pCR (OR 0.75 (95% c.i. 0.38 to 1.46) (P = 0.404)). There were significant differences in axillary pCR rates between breast cancer molecular subtypes. The lowest probability (7%) was found for hormone receptor+/human epidermal growth factor receptor 2− tumours. Using this category as a reference group, significantly increased ORs of 14.82 for hormone receptor+/human epidermal growth factor receptor 2+ tumours, 40 for hormone receptor−/human epidermal growth factor receptor 2+ tumours, and 6.91 for triple-negative tumours were found (P < 0.001).ConclusionMolecular subtype is a significant predictor of axillary pCR after neoadjuvant systemic therapy, whereas axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT is not.

Background and Purpose: There is currently lack of recognized imaging criteria for prediction of treatment response to NAST in breast cancer patients. And early identification of treatment response to neoadjuvant systemic therapy (NAST) in Triple Negative Breast Cancer (TNBC) patients is important for appropriate treatment selection and response monitoring. A novel MRI sequence, Magnetic Resonance Image Compilation (MagIC) is capable of simultaneous quantitation of several tissue water properties including longitudinal (T1), transverse (T2) relaxation times, and proton density (PD). In this study we evaluated the ability of a radiomic model extracted from a novel MagIC sequence acquired early during NAST to predict pathologic complete response to NAST in TNBC. Materials and Methods: This IRB approved prospective ARTEMIS trial (NCT02276443) included 184 women (122 training dataset, 62 testing dataset) diagnosed with stage I-III TNBC. All patients were scanned with MagIC on a 3T MRI scanner at baseline (184 patients), and after 4 cycles (156 Patients) of NAST. T1, T2 and PD maps were generated from the source images using SyMRI (SyntheticMR, Linkoping, Sweden). Histopathology at surgery was used to determine pathologic complete response (pCR) which was defined as absence of the invasive cancer in the breast and axillary lymph nodes. 3D contouring of the tumors was performed using an in-house toolbox. 310 (10 first-order, 300 GLCM) textural features were extracted from each map, with total of 930 features/patient. Radiomic features were compared between pCR and non-pCR using Wilcoxon Rank Sum test and Fisher’s exact test. To build a multivariate, predictive model, logistic regression with elastic net regularization was performed for texture feature selection. The tuning parameter was optimized using 5-fold cross-validation based on the average area under curve (AUC) of each fold of a cross-validation using training data. Then the testing data were used to compare model’s performance by AUC. Results: Univariate analysis found 23 PD, 17 T1 and 10 T2 radiomic features at C4 time point to be able to predict pCR status with AUC &amp;gt;70% in both training and testing cohort. The top performing radiomic features were Entropy, Variance, Homogeneity and Energy (Tables1-2). Multivariate radiomics models from C4-PD, and C4-T1 maps showed best performance during both cross validation and independent testing. The radiomic signature of C4-T1 map that included 27features had best performance, with an AUC of 0.77, 0.70 (95% CI: 0.571-0.868) in training and testing cohort respectively. C4-PD map radiomic signature that included 6features was able to predict the pCR status with AUC of 0.73, 0.72 (95% CI: 0.571-0.868) in training and testing cohort respectively. Conclusion: Our data found that MagIC-based radiomics signature could potentially predict pathologic complete response in TNBC early during NAST. This data shows the potential application of MagIC radiomic model for improvement of response assessment in TNBC. Table 1.Best performing radiomic features from PD map after 4 cycles of NAST in TNBC patients.FeatureTraining CohortTraining CohortTraining CohortTesting CohortTesting CohortTesting CohortNAUC95% CINAUC95% CIP-valuePD-mapAngular Variance of Sum entropy1060.73820.6437-0.8328500.73240.5895-0.8752&amp;lt;0.001Range of Sum entropy1060.73930.6446-0.834500.72120.5753-0.867&amp;lt;0.001Angular Variance of Sum entropy1060.75960.6662-0.853500.70190.5538-0.8501&amp;lt;0.001Average of Sum entropy1060.73470.6367-0.8327500.70990.5613-0.8585&amp;lt;0.001Angular Variance of Sum variance1060.70160.602-0.8011500.70190.5543-0.8495&amp;lt;0.001Range of Sum variance1060.70050.6001-0.8009500.700.5499-0.8476&amp;lt;0.001 Table 2.Best performing radiomic features from T1-T2 maps after 4 cycles of NAST in TNBC patients.FeatureTraining CohortTraining CohortTraining CohortTesting CohortTesting CohortTesting CohortNAUC95% CINAUC95% CIP-valueT1-mapAngular Variance of Sum entropy1060.76530.6762-0.8544500.70510.5524-0.8579&amp;lt;0.001Range of Sum entropy1060.76530.6759-0.8547500.70350.5503-0.8567&amp;lt;0.001Average of Entropy1060.75250.6568-0.8482500.71630.572-0.8607&amp;lt;0.001Average of Sum entropy1060.750.6552-0.8448500.70190.555-0.8488&amp;lt;0.001Angular Variance of Energy1060.7450.6493-0.8407500.73080.59-0.8715&amp;lt;0.001Range of Energy1060.74290.6466-0.8392500.72920.5885-0.8699&amp;lt;0.001Average of Energy1060.74110.6438-0.8384500.7260.5852-0.8667&amp;lt;0.001Average of Entropy1060.73360.635-0.8322500.74040.602-0.8787&amp;lt;0.001Average of Maximum probability1060.70760.6054-0.8098500.71630.5704-0.8623&amp;lt;0.001Range of Maximum probability1060.70550.6018-0.8092500.75640.6195-0.8933&amp;lt;0.001T2-mapAngular Variance of Energy1060.74820.6531-0.8433500.70990.5644-0.8555&amp;lt;0.001Range of Energy1060.7450.6495-0.8405500.70350.5569-0.8501&amp;lt;0.001Average of Entropy1060.74070.6416-0.8399500.72920.585-0.8733&amp;lt;0.001Average of Sum entropy1060.73860.6405-0.8367500.72440.5797-0.869&amp;lt;0.001Average of Energy1060.73180.6309-0.8327500.72120.5743-0.86&amp;lt;0.001Angular Variance of Sum entropy1060.7290.631-0.827500.72760.5857-0.8695&amp;lt;0.001Range of Sum entropy1060.72760.6295-0.8257500.72280.5796-0.8659&amp;lt;0.001Average of Information measure of correlation 11060.71580.6147-0.8169500.70990.5638-0.8561&amp;lt;0.001Average of Entropy1060.700.5903-0.8028500.74360.6014-0.8858&amp;lt;0.001 Citation Format: Nabil Elshafeey, Ken-Pin Hwang, Beatriz Elena Adrada, Rosalind Pitpitan Candelaria, Medine Boge, Rania M Mahmoud, Huiqin Chen, Jia Sun, Wei Yang, Aikaterini Kotrotsou, Benjamin C Musall, Jong Bum Son, Gary J Whitman, Jessica Leung, Huong Le-Petross, Lumarie Santiago, Deanna Lynn Lane, Marion Elizabeth Scoggins, David Allen Spak, Mary Saber Guirguis, Miral Mahesh Patel, Frances Perez, Abeer H Abdelhafez, Jason B White, Lei Huo, Elizabeth Ravenberg, Wei Peng, Alastair Thompson, Senthil Damodaran, Debu Tripathy, Stacey L Moulder, Clinton Yam, Mark David Pagel, Jingfei Ma, Gaiane Margishvili Rauch. Radiomics model based on magnetic resonance image compilation (MagIC) as early predictor of pathologic complete response to neoadjuvant systemic therapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD11-06.

Purpose Basal-like breast cancer, as defined by gene expression profiling, is associated with aggressive phenotype and poor clinical outcome. Recent immunohistochemical validation suggested that basal-like subtype could be characterized by staining for cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) in triple negative breast cancers (TNBCs). Most of studies evaluated surrogate immunopannel of biomarkers to define basal-like breast cancer subtypes only in the TNBCs, although not all basal-like breast cancers are triple negative breast cancers (TNBCs). The significance of basal marker expression in other than triple negative breast cancer remains to be evaluated. To define prognostic impact of basal marker expression in HER2 positive breast cancer, we investigated cytokeratin (CK) 5/6 and epidermal growth factor receptor (EGFR) expression in patients with HER2 positive early breast cancer. Patients and Methods: Biomarker evaluation was performed using five immunohistochemical surrogate panel of estrogen receptor (ER), progesterone receptor (PR), HER2, CK 5/6 and EGFR in HER2 positive early breast cancers. Amplification of HER2 was confirmed by fluorescent in situ hybridization. HER2-positive breast cancer was classified by expression of basal markers (either EGFR or CK5/6) as “basal HER2- positive” (patients with HER2- positive disease who express basal markers) and “non-basal HER2” (patients with HER2-positive disease who did not express basal markers). We compared the prognostic significance of the basal marker expression between two groups. RESULTS: HER2 overexpression was found in 24.8% of early breast cancers with available tissue specimens from the primary tumor (236 of 952 cases). Basal marker co-expression was identified in 12.7% of HER2 positive early breast cancers. (30 of 236 patients) Basal HER2 positive breast cancer was significantly associated with age greater than 50 years (P=0.012), absence of ER (P &amp;lt; 0.001) and PR (P=0.004). The basal marker co-expression in patients with HER2 amplified early breast cancers demonstrated poorer overall survival (basal positive vs. basal negative, 85.6 months [95% confidence interval (CI), 70.8- 100.3 months] vs. 122.3 [C.I. 133.7-139.9], P=0.001) and disease free survival (DFS) (44.6 months [95% CI, 14.7-74.8] vs 110.7 months [95% CI, 96.4-123.9]; P=. 008) respectively. In lymph node positive group, basal marker expression retained its statistical significance at the multivariate level (P=0.047) HER2 positive breast cancer with lymph node involvement with basal marker expression showed substantially poorer overall survival with 2.1-fold (95% CI, 1.0-4.2) risk for death. CONCLUSION: Considerable number of HER2 positive breast cancer co-expressed basal markers. Our data demonstrated that simultaneous basal marker expression in HER2 positive early breast cancer is associated with poor clinical outcome. The molecular significance of basal marker expression in HER2 positive breast cancer needs to be further investigated. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-03.

Background: Tumor-infiltrating lymphocytes (TILs) reflect host immune response and are associated with prognosis and treatment response in HER2-positive and triple-negative breast cancer (TNBC). While the International Immuno-Oncology Biomarker Working Group recommends evaluating stromal TILs in tumor areas, intratumoral heterogeneity and small sample size in core needle biopsy (CNB) specimens limit consistent assessment. It remains unclear whether central tumor (CT) or invasive margin (IM) regions should be prioritized and what cut-off values are clinically relevant. Ultrasonographic (US) features may also reflect the immune microenvironment. We previously proposed a TILs-US score based on three US features that predicts lymphocyte-predominant breast cancer (LPBC). This study evaluated the clinical utility of TILs assessment from CT and IM regions, appropriate cut-off values for predicting response in HER2-positive and TNBC using CNB, and explored optimal biopsy targeting through pathologic and US comparisons. Methods: In this multicenter retrospective study, we analyzed 239 patients (124 HER2-positive, 115 TNBC) with cT1-3/cN0-2 breast cancer who underwent surgery after neoadjuvant chemotherapy (NAC). TILs were evaluated using CNB specimens obtained before NAC and assessed separately in the central tumor (CT) and invasive margin (IM) regions. The IM was defined as a 1-mm-wide area centered on the interface between the tumor and surrounding stroma, while the CT was defined as the remaining intratumoral area within the IM boundary. TILs were analyzed using binary cut-offs of 30% and 50%, as well as a three-tier classification: low (0-10%), intermediate (11-49%), and high (≥50%). Pre-treatment ultrasound (US) findings included tumor shape (scored 0-2), internal echo (0-2), and posterior echo (0-3), which were used to calculate a composite TILs-US score ranging from 0 to 7. Associations between TIL levels, US features, and pathological complete response (pCR) were analyzed. Results: Overall, 104 patients achieved pCR (HER2-positive: 39; TNBC: 65). Using a 30% cut-off, TILs were evenly distributed both CT and IM, while ≥50% cases were relatively rare especially CT (CT: 10%; IM: 20%). CT TILs ≥30% was significantly associated with pCR (p=0.001), whereas the ≥50% cut-off was not (p=0.128). In contrast, both 30% and 50% cut-offs in the IM region were predictive of pCR (p&amp;lt;0.001 and p=0.009, respectively). Subtype analysis revealed that in TNBC, TILs ≥30% in both CT and IM regions were significantly correlated with pCR. In HER2-positive cases, however, only IM TILs ≥30% was predictive of pCR. Similar trends were observed with the three-tier classification. Among US features, a small lobulated shape was associated with high TILs levels in both CT and IM regions, while an enhanced posterior echo was correlated with high TILs in the IM region. Conclusion: Our findings suggest that TILs assessment should include the IM in addition to the CT, especially in CNB specimens as provide valuable information. Given the limited tissue area available in CNB specimen, using a 30% cut-off for TILs may offer a clinically meaningful threshold to predict treatment response. In cases where US findings suggest central fibrosis, targeting only the tumor center may result in sampling fibrotic areas with sparse immune and tumor cells, potentially hindering proper evaluation. Therefore, selecting the biopsy target based on US imaging is essential. Especially in HER2-positive breast cancer, as well as TNBC, it is important for operators to consider the optimal needle insertion angle and sampling site to ensure appropriate sampling of viable tumor tissue and immune microenvironment for accurate pathological and immunological evaluation. Citation Format: Y. Kimura, R. Yamaguchi, K. Fukui, A. Kanou, M. Noma, S. Akashi-Tanaka, K. Arihiro, N. Iwamoto, Y. Ohta, T. Okuno, S. Kashiwagi, Y. Kamei, Y. Tanada, S. Nakano, A. Nagata, A. Murakami, Y. Mochitomi, A. Yamakawa, M. Yamaguchi, H. Shima, A. Emi. Ultrasound-guided biopsy-based tils assessment at tumor margins as a predictive biomarker of neoadjuvant treatment response in early her2-positive and triple-negative breast cancer: a multicenter study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-18.

Background The real-world risk of disease recurrence in patients with HER2-positive early breast cancer who achieved pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) and/or HER2-targeted therapy is unclear. This study aims to identify the patterns and risk factors of disease recurrence after NAC in patients with HER2-positive early breast cancer who achieved a pCR or not. Methods 930 HER2 positive early breast cancer patients who received NAC were identified in the Severance Breast Cancer Registry at the Yonsei Cancer Center and Gangnam Severance Hospital in Seoul, Republic of Korea, between 2006 and 2020. NAC included 3 regimens: only chemotherapy. (CTx), chemotherapy plus trastuzumab (CTx+H), and chemotherapy plus dual anti-HER2 therapy (TCHP). The pCR was defined as the absence of residual invasive cancer in the resected breast specimen and the axillary lymph nodes (ypT0/TisN0) after neoadjuvant systemic therapy. Recurrence of disease was defined as recurrence of ipsilateral locoregional invasive breast cancer, distant disease recurrence, or death. Results The median follow-up duration was 42.0 months (range 4-171), and median age was 51 years old (range 22-80). The rate of pCR was 52.2% (485/930). Depending on the achieved a pCR, the loco-regional recurrence rate was 4.0% (18/445) vs 1.0% (5/485), and the distant recurrence rate was 11.0% (49/445) vs 3.9% (19/445). Of the 79 patients who relapsed, 30.4% (n=24) had achieved a pCR and 69.6% (n=55) had residual disease. The 4-year recurrence risk was 6.9% for patients who achieved pCR versus 12.8% for those who did not (p&amp;lt;0.001). Of the 24 patients who achieved pCR who relapse, 22 (91.7%) occurred within 4 years of diagnosis. Of the 55 patients who did not achieve a pCR who relapse, 48 (87.3%) occurred within 4 years of diagnosis. Among the 19 patients who developed distant recurrence who attained a PCR, the most common first recurrent sites were lung (42.1%), brain (36.8%), and distant lymph nodes (36.1%). Lung and brain metastases occurred in 87.5% and 85.7% within 3years of diagnosis. If pCR was reached, the NAC regimen or HR status did not affect the recurrence-free survival. However, clinical stages II and III at diagnosis (HR (hazard ratio) =35.3 and HR=114.5, p=0.037) were independent predictor of inferior recurrence-free survival in the pCR group. Conclusion Overall, patients who attained a pCR have a better outcome compared to those with residual disease, regardless of hormone status or type of NAC regimen. However, despite achieving pCR after NAC, patients with HER2-positive, clinical stage II/III remain at risk for disease recurrence within 4 years of diagnosis. Citation Format: Jee Hung Kim, Jii Bum Lee, Soong Joon Bae, Sung Gwe Ahn, Joon Jeong, Min Hwan Kim, Seul-Gi Kim, Gun Min Kim, Jee Ye Kim, Hyung Seok Park, Seho Park, Byeong Woo Park, Seung Il Kim, Joohyuk Sohn. Pattern of recurrence after pathologic complete response after neoadjuvant chemotherapy in patients with early HER2-positive breast cancer: Real-world evidence [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-14.

Neoadjuvant systemic therapy (NAST) has become an established treatment option for women with operable breast cancer. We aimed to better understand NAST treatment patterns, barriers and facilitators in Australia and New Zealand. We undertook a cross-sectional survey of the current clinical practice of Australian and New Zealand breast cancer specialists. Questions included referral patterns for NAST, patient selection, logistics, decision making and barriers. Of 207 respondents, 162 (78%) reported routinely offering NAST to selected patients with operable breast cancer (median 9% of patients offered NAST). Specialty, location, practice type, gender or years of experience did not predict for offering NAST. In all, 45 and 58% wanted to increase the number of patients who receive NAST in routine care and in clinical trials respectively. Facilitators included the multidisciplinary team meeting and access to NAST clinical trials. Specialist-reported patient barriers included: patient desire for immediate surgery (63% rated as important/very important); lack of awareness of NAST (50%); concern about progression (43%) and disinterest in downstaging (32%). Forty-three per cent of participants experienced system-related barriers to the use of NAST, including other clinicians' lack of interest (27%); lack of clinical trials (24%) and unacceptable wait for a medical oncology appointment (37%). This group of Australian and New Zealand clinicians are interested in NAST for operable breast cancer in routine care and clinical trials. Patient- and system-related barriers that prevent the optimal uptake of this treatment approach will need to be systematically addressed if NAST is to become a more common approach.

Predictive and prognostic value of stromal tumour-infiltrating lymphocytes before and after neoadjuvant therapy in triple negative and HER2-positive breast cancer

Simple SummaryPrimary systemic or neoadjuvant chemotherapy of breast cancer has become a standard therapy option in locally advanced or triple negative or Her2 positive breast cancer. Neoadjuvant chemotherapy can result in complete pathological response without residual tumor cells (tumor bed) or partial response and non-response with different amounts of reactive stroma and residual tumor cells. In this study, we characterized the mutational status of residual breast cancer cells and reactive tumor stroma devoid of residual tumor cells in partial or non-responders using next generation sequencing. Pathogenic driver-mutations are exclusively restricted to residual carcinoma cells and are absent in reactive stroma independently from intrinsic breast cancer subtypes or tumor stage. These data suggest that the absence of pathogenic mutations in a tumor bed without residual tumor cells may have prognostic implications after neoadjuvant chemotherapy. Primary systemic or neoadjuvant chemotherapy of breast cancer has become a standard therapy option in locally advanced or predefined intrinsic subtypes such as triple negative or Her2 positive breast cancer. Neoadjuvant chemotherapy can result in complete pathological response without residual tumor cells (tumor bed) or partial response and non-response with different amounts of reactive stroma and residual tumor cells. The interaction between therapy regimens and tumoral driver mutations have been extensively studied, although the reactive stroma of the tumor bed received less attention. In this study, we characterized the mutational status of residual breast cancer cells and reactive tumor stroma devoid of residual tumor cells in partial or non-responders using next generation sequencing. Twenty-one post-therapeutic breast surgical specimens after neoadjuvant chemotherapy underwent pathogenic driver-mutation screening using microdissected residual breast cancer cells and in reactive stroma adjacent to tumor bed areas. In reactive stroma, no mutations could be validated. In residual breast cancer cells, mutations were detected in sixteen of twenty-one cases (76%). In nine of these twenty-one cases (43%), pathogenic driver mutations (PIK3CA, PTEN, TP53, FN1, PLAG1) were identified. Pathogenic driver-mutations are exclusively restricted to residual carcinoma cells and are absent in reactive stroma independently from intrinsic breast cancer subtypes or tumor stage. These data suggest that the absence of pathogenic mutations in a tumor bed without residual tumor cells may have prognostic implications after neoadjuvant chemotherapy.

Neoadjuvant systemic therapy for breast cancer patients means systemic treatments before operations.Combination chemotherapy,endocrine therapy and targeted therapy before operation can degrade the tumor staging and increase the breast-conserving rates.Neoadjuvant chemotherapy has been accepted as one of the standard therapies for patients with locally advanced breast cancers.In the neoadjuvant setting,the studies about the use of aromatase inhibitors and trastuzumab in selected patients have also made great progresses. Key words: Breast neoplasms; Neoadjuvant therapy; Drug therapy; Endocrine therapy; Targeted therapy

The 15th St Gallen International Breast Cancer Conference was held in Vienna for the second time, from 15th–18th March 2017. 4000 people from 105 countries all over the world were invited to take part in the event. The real highlight of the conference was the last day with the International Consensus Session which was chaired by around 50 experts on breast cancer worldwide. With reference to data from scientific research, the consensus panel tried to offer guidelines for the management of breast cancer with the aim of providing patients with optimal treatment. The topics covered focused on the treatment of breast cancer, consideration of surgery, radiotherapy, neo-adjuvant, and adjuvant systemic therapy for breast cancer, as well as genetics and prevention of breast cancer.In particular, in terms of precision medicine, an important topic of the conference was ‘is it possible to think that it could become routine in clinical practice to use immunotherapy and targeted therapy based on genetic signatures?’In view of personalised therapy, it is important to take into consideration women’s treatment preferences. It is also important not only to offer guidelines which help breast cancer experts all over the world to choose the proper treatment for women with breast cancer but also to discuss the pros and cons of the therapy with the patient. This allows for a better understanding of the disease.‘From the maximum tolerable to the minimum effective treatment: it is essential to escalate treatment when necessary and to de-escalate when unnecessary’. These few words could summarise the meaning of the 15th St Gallen International Breast Cancer Conference. Prof Martine Piccart-Gebhart was awarded with the St Gallen International Breast Cancer Award 2017 for her fundamental clinical research contribution and Prof Giuseppe Curigliano with the Umberto Veronesi Memorial Award which aims to recognise a physician’s leading role in advancing the science and care of breast cancer patients. Curigliano, in his lecture, spoke about the revolutionary immunotherapy in the clinical management of breast cancer (BC). For the development of these therapies, it is necessary to identify the genetic determinants of BC immune phenotypes in which The Cancer Genome Atlas (TCGA) has contributed towards this.For example, the T helper (Th-1) phenotype (ICR4), which also exhibits upregulation of immune-regulatory transcripts (eg. PDL1, PD1, FOXP3, IDO1, and CTLA4), was associated with prolonged patients’ survival. Chromosome segment 4q21, which includes genes encoding the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favourable phenotype (ICR4). The mutation and neo-antigen load progressively decreased from ICR4 to ICR1 but could not explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favourable phenotype (ICR4). Instead, the presence of MAP3K1 and MAP2K4 mutations were closely associated with an immune unfavourable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates BC according to their immune disposition. These findings suggest that mutational-driven deregulation of MAPK pathways is linked to the negative regulation of intratumoural immune response in BC.The main themes of this congress were: 1) Surgery of the primary tumour and margins; 2) Surgery of the axilla; 3) Radiotherapy: hypofractionated, ‘boost’ to tumour bed, partial breast, regional node, after mastectomy, advanced technology; 4) Pathology: subtypes, TILs; 5) Multi-gene signatures and therapy; 6) Endocrine therapy: pre- and post-menopausal and duration; 7) Chemotherapy: subtypes, stages; 8) Anti-HER-2 therapy; 9) Neo-adjuvant therapy; 10) Adjuvant bisphosponates; 11) Adjuvant diet and exercise.