Clinicopathologic Characteristics of Breast Cancer Patients Who Had a Pathologic Complete Response after Neoadjuvant Treatment.

Background Neoadjuvant therapy is increasingly utilised in early and locally advanced breast cancer to improve operability and provide an early in vivo assessment of treatment response. Achieving pathological complete response (pCR) is associated with improved long-term outcomes, particularly in HER2-positive and triple-negative breast cancer (TNBC). While major trials have reported neoadjuvant therapy outcomes by tumour subtype, real-world data from regional centres remain limited. This study evaluates pCR rates, treatment completion, and treatment-related toxicities in a regional Australian cohort receiving neoadjuvant therapy for breast cancer. Methods A retrospective audit was conducted of all female patients with early or locally advanced breast cancer who received neoadjuvant systemic therapy followed by surgery at Goulburn Valley Health, Victoria, between January 2020 and May 2025. Data collected included demographics, tumour subtype, treatment details, hospitalisations during therapy, and rate of pathological complete response. Results 70 patients underwent neoadjuvant therapy at Goulburn Valley Health. Subtypes included HER2-positive (n=28), triple-negative breast cancer (TNBC; n=26), and hormone receptor-positive/HER2-negative (HR+/HER2−; n=16). 47 patients (67.1%) completed their planned neoadjuvant therapy. 21 patients (30%) required hospital admission during their neoadjuvant therapy. Surgical procedures after therapy included breast-conserving surgery in 36 patients, single mastectomy in 25, and bilateral mastectomy in 8 patients. 1 TNBC patient did not proceed to surgery due to disease progression. Pathologic complete response (pCR) rates were 42.9% (12/28) in HER2-positive, 38.5% (10/26) in TNBC, and 6.3% (1/16) in HR+/HER2− patients. Notable differences in pCR rates were observed between patients who completed neoadjuvant therapy and those who did not. In the HER2-positive group, 57.1% (12/21) of patients who completed therapy achieved pCR, compared to 0% (0/7) among non-completers. In the TNBC group, pCR was achieved in 50% (8/16) of patients who completed therapy versus 20% (2/10) of patients who did not. Conclusion This regional Australian cohort demonstrates pCR rates comparable to published literature, with a higher pCR rate seen in HER2+ and TNBC subtypes versus HR+/HER2−. Completion of the planned neoadjuvant therapy regimen was associated with increased pCR rates in both TNBC and HER2-positive subgroups. These findings highlight the importance of supportive care to minimise treatment interruptions, aiding in neoadjuvant therapy completion. Citation Format: D. Bu, J. Torres, A. Sahu. Real-world outcomes of neoadjuvant therapy for breast cancer: a regional australian cohort 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 PS5-05-12.

Pertuzumab-based neoadjuvant chemotherapy (NAC) has demonstrated successful pathologic complete response (pCR) rates when administered to patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced breast cancer and has become standard of care. This study aimed to identify pCR rates in patients receiving a variety of pertuzumab-based NAC regimens. The effect of the addition of an anthracycline and impact of anthracycline and taxane sequencing on pCR was also assessed. A retrospective, single-center review was conducted on patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer that received one of five pertuzumab-containing NAC regimens followed by definitive surgery. Ninety-six patients were included in the analysis; overall, pCR was attained in 49 patients (51%). Of the 61 patients who received an anthracycline-containing NAC regimen, 30 (49%) attained a pCR. Of the 35 patients who received the non-anthracycline NAC regimen, 19 (54%) attained a pCR; difference in pCR was not statistically significant (p = 0.63). Anthracycline/taxane sequence analysis showed that of the patients attaining pCR with an anthracycline-containing NAC, 77% of patients received the taxane portion upfront (p = 0.17). Relative dose intensity of the anthracycline portion was similar irrespective of treatment sequence. However, relative dose intensity of the taxane portion was decreased with upfront anthracycline administration. These findings support current recommendations of adding pertuzumab to established regimens for treatment of locally advanced, HER2-positive, early stage breast cancer. The benefit of adding an anthracycline in the neoadjuvant setting remains unclear. Patients treated with the taxane portion of NAC upfront appeared to have a higher rate of pCR and better relative dose intensity than patients who received the anthracycline portion upfront, but differences were not statistically significant. These findings should be verified in a prospective clinical trial.

Multidisciplinary considerations in the treatment of triple-negative breast cancer.

11590 Background: Reducing the primary tumor volume and increasing the breast conserving surgery (BCS) rate are the main roles of neoadjuvant chemotherapy (NAT) in breast cancer. The aim of this study was to evaluate the benefit in adding docetaxel to anthracycline neoadjuvant therapy for breast cancer. Methods: Retrospective cohort study comparing the efficacy of NAT for breast cancer in patients subjected to docetaxel (75mg/m2) and epirubicin (60mg/m2) or 5-fluorouracil (600mg/m2), epirubicin (60mg/m2) and cyclophosphamide (600mg/m2) combinations (DE and FEC group, respectively). The mean number of chemotherapy delivered was three (2 to 6) in both groups (p= 0.8). Forty-six patients in the FEC group and 90 patients in the DE group were clinical stage II. Stage III was observed in 95 and in 68 patients in the FEC and the DE groups, respectively. The primary endpoint was the clinical and pathologic response to primary chemotherapy. The BCS rate was compared. Results: In stage II patients, the objective clinical response (OR) rate was 70% in the FEC group and 81% in the DE group, and the complete clinical response was in 11% and 29% in the FEC and DE groups, respectively (p= 0.01). The complete pathologic response (pCR) rate was 2% in the FEC group and 14% in the DE group (p= 0.01). In stage III patients, the objective clinical response rate was 49.5% in the FEC group and 80% in the DE group with complete clinical response rate of 9.5% and 13% in FEC and DE groups, respectively (p= 0.0001). The complete pathologic response (pCR) rate was 3.3% and 7.7% in FEC and DE groups, respectively (p= 0.1). BCS rate was higher in patients treated with DE scheme (67.5% versus 53% in stage II patients; p= 0.002, and 43.5% versus 29.5% in stage III patients; p= 0.0003). Conclusions: The NAT with DE combination is more effective in terms of clinical and pathologic response propitiating higher BCS rate than the FEC combination in stage II and III breast cancer. No significant financial relationships to disclose.

Is there still a role for neoadjuvant therapy in breast cancer?

Introduction: Neoadjuvant breast cancer therapy trials have documented impressive rates of pathologic complete response (pCR) of up to 70% and above, depending on grade, hormone receptor and HER2 receptor status and type of therapy. The purpose of our prospective single institution trial is to examine the predictive value of a standardized vacuum assisted core-needle biopsy (VAB) of the tumor site after neoadjuvant therapy with respect to pathologic response status. Methods: From 2011-2017, all patients who had completed neoadjuvant breast cancer therapy at our institution were informed about this trial regardless of their clinical response status. In case of consent, a VAB of the clip-marked tumor site was performed directly before the operation. At least 3, in most cases 6 biopsy cylinders were obtained. Results: A total of 113 patients completing neoadjuvant therapy consented to the trial. Four patients presented with bilateral breast cancer, resulting in 117 cases of breast cancer. The pCR rate (ypT0ypN0) was 36% (n=42). In 14 cases, the biopsy did not show any sign of residual disease, although residual disease was detected upon operation, resulting in an accuracy of 88% for correct prediction of pathologic response. Pre-operative VAB correctly predicted residual tumor in 81%. The negative predictive value was 75%. Conclusions: Although the results of this trial are encouraging, a false negative rate of 19% is entirely insufficient. The method may be useful in guiding decisions regarding the modification of neoadjuvant therapy based on pathological response. Whether or not correct prediction of pathologic response may be improved by further standardizing the tumor marking procedure as well as better defining and increasing the volume of tissue removal by VAB should be examined in a further prospective trial. The omission of operative therapy in case of pCR in a preoperative biopsy after completion of NACT cannot be recommended. Citation Format: Regina Große, Antonia Lebioda, Jana Saegenschnitter, Tin Dao Nguyen, Holger Zentgraf, Joerg Buchmann, Christine Fathke, Susanne Steer, Christoph Thomssen. Vacuum assisted core-needle biopsy after neoadjuvant therapy in breast cancer to predict the status of pathologic response [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-03-01.

Background Breast cancer is relatively rare in women younger than 35 years of age, accounting for 2–4% of the total number of breast cancer cases diagnosed each year in western countries and the USA 1–3. However, the proportion of young age-onset breast cancer was much higher in the Asian population 3–6. Breast cancer at a young age has been reported to have a more aggressive biological behavior and to be associated with worse prognosis compared with the disease in older patients 5,7–17. Higher incidence of recurrence and risk of death were detected in younger patients, even when more aggressive therapies were administered 10–14. Neoadjuvant chemotherapy (NCT) has been considered the standard treatment for locally advanced breast cancer patients. In human epidermal growth factor receptor 2 (HER2)-positive and triple-negative tumors, achievement of a pathological complete response (pCR) after NCT was associated with better survival outcomes 18. In recent studies, young breast cancer patients were reported to obtain higher pCR rates compared with older counterparts 19,20. However, it remains unclear whether pCR is a predictor for better prognosis in young breast cancer patients. In this study, we aimed to investigate chemotherapy response and its relation with prognosis in young breast cancer patients (<35 years old) who were treated with NCT. Patients and methods Patients From January 2003 to December 2013, patients with operable or locally advanced breast cancer who were treated with NCT at the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College were reviewed systemically. The inclusion criteria for the study were as follows: (i) 35 years or younger or 60 years or older; (ii) diagnosis of invasive carcinoma confirmed by core needle biopsy before NCT and the lymph node status was evaluated by fine needle aspiration of palpable lymph node if applicable; (iii) immunohistochemical examination for estrogen receptor (ER), progesterone receptor (PgR), and HER2 status using tumor specimens from core needle biopsy; (iv) newly diagnosed breast cancer patients; (v) combination of paclitaxel and carboplatin (PC) in patients with triple-negative breast cancer as NCT; for other patients, a combination of cyclophosphamide and epirubincin (CE) as NCT with postoperative paclitaxel, or epirubincin in combination with paclitaxel (ET) as NCT 21; (vi) adequate hematologic, hepatic, and renal functions. The exclusion criteria for the study were as follows: (a) stage IV disease, bilateral breast cancer, male breast cancer, and patients complicated with other malignancies; (b) patients who did not have complete clinical information or immunohistochemistry; (c) patients who were lost to follow-up immediately after treatment. This study was a retrospective observational research and patients' information was collected in the hospital database. There was no direct intervention in patients' treatment or care. Therefore, a patient's consent was not required. This study was approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College. Treatment Before the initiation of NCT, bilateral breast MRI or ultrasound, chest radiography, abdominal ultrasound, or computed tomography scans were performed to determine clinical stage. All patients were staged according to the 7th TNM (tumor–node–metastasis) staging system maintained by the American Joint Committee on Cancer (AJCC). All patients received NCT with CE, or ET, or PC regimens. CE-T regimen: cyclophosphamide 600 mg/m2 intravenously, day 1, and epirubicin 80 mg/m2 intravenously, day 1, q14d×4 cycles in NCT, followed by postoperative sequential paclitaxel 175 mg/m2 intravenously, day 1, q14d×4 cycles; ET regimen: epirubincin 75 mg/m2 intravenously, day 1, and paclitaxel 175 mg/m2 intravenously, day 2, q21d×4 cycles as NCT; and two cycles of ET regimen were repeated after surgery; PC regimen: paclitaxel 175 mg/m2 intravenously, day 1, and carboplatin area under the curve=5 intravenously, day 1, q21d×6 cycles as NCT. Mastectomy or breast-conserving surgery was performed within 1 month after the completion of NCT. Adjuvant radiotherapy was prescribed at the discretion of physicians mainly on the basis of the TNM stage before NCT, followed by endocrine therapy in cases with ER-positive or PgR-positive tumors. Trastuzumab was recommended in HER2-positive patients, but not compulsory. Efficacy evaluation Clinical efficacy was estimated every two cycles by clinical, mammographic, B-ultrasound examinations, and MRI according to Response Evaluation Criteria in Solid Tumors 1.1 criteria. Pathological efficacy was assessed by pathologic report after surgery and imaging data. Efficacy evaluation indicators included pCR, clinical complete response (CR), clinical partial response (PR), overall objective response rate (ORR=CR+PR), clinical progressive disease (PD), and clinical stable disease (SD). pCR was defined as no histological evidence of malignancies or only in-situ residuals in breast tissue after surgery, and complete disappearance of lymph node metastasis. CR was defined as disappearance of all known lesions. PR was defined as at least a 30% decrease in the sum of the largest diameters of target lesions. PD was defined as at least a 20% increase in the sum of the largest diameters of target lesions or new lesions detected. SD was defined as a reduction in the largest sum diameters of tumors by no more than 30% or an increase of no more than 20%. Patients with overall objective response rate received planned treatment and sequential surgery. Patients who fulfilled the criteria for SD or PD at the initial efficacy evaluation received surgery as soon as possible and were then treated with alternative postoperative regimens. Statistical analysis All data were analyzed using SPSS medical statistical software (version 15.0; SPSS Inc., Chicago, Illinois, USA). Disease-free survival (DFS) was defined as the period from the date of receiving NCT to the date of recurrence or metastasis or last follow-up; overall survival (OS) was defined as the period from the date of receiving NCT to the date of death for any cause or last follow-up. Both OS and DFS were analyzed using the Kaplan–Meier method. Comparisons of OS or DFS between groups were performed using the log-rank test. A two-tailed P value less than 0.05 was considered statistically significant. The χ2 or Fisher's exact test was performed to compare the clinicopathological variables and pCR rates between the subgroup of younger than 35 years of age and the subgroup of older than 60 years of age. Results Patient characteristics and treatment From January 2003 to December 2013, a total of 141 breast cancer patients were enrolled in this study and 74 (52.5%) of these patients were younger than 35 years old. As shown in Table 1, younger patients presented a tendency to have a tumor size of more than 5 cm (P=0.085), to have axillary positive nodes (P=0.118), and to have lymphovascular invasion (P=0.007) compared with their older counterparts (≥60 years old). As for the treatment, younger patients were more likely to choose breast-conserving surgeries (P=0.024) and to receive adjuvant radiotherapy after surgeries (P<0.001). For the entire cohort, the median number of NCT cycles was 4 (range: 4–6 cycles). The chemotherapy regimens were changed for a total of 31 patients who had a poor response to preoperative chemotherapies (including 26 SD and five PD). Overall, 52% (16/31) of these patients were in the young group, and the other 15 patients were older than 60 years. All 96 patients with preoperative or postoperative pathological ER-positive or PgR-positive breast cancer received different postoperative adjuvant endocrine therapies. In all, 18.9% (14/74) of patients in the young group and 16.4% (11/67) of patients in the old cohort received 1 year of trastuzumab after surgery or adjuvant chemotherapy.Table 1: Patients' baseline characteristicsTreatment response All patients were evaluable for response to NCT. The rates of pCR, clinical PR (except clinical PR, but confirmed as pCR finally), clinical SD, and clinical PD were 12.8% (18/141), 65.2% (92/141), 18.4% (26/141), and 3.5% (5/141), respectively. pCR rates were similar between the young group and the old cohort (12.2 vs. 13.4%, P=0.821). The PC regimen tended to yield higher pCR rates in the young cohort, but this was not statistically significant. HER2-positive or inflammatory breast cancer patients in young group were also more likely to achieve pCR compared with their older counterparts. As shown in Table 2, there were no significant differences between the pCR rates of young and old patients across various subgroup analyses, including hormone receptor status, axillary lymph node metastasis from primary tumors, primary tumor size, HER2 expression status, and NCT regimens.Table 2: Clinical and pathological factors affecting pathological complete response ratesSurvival analysis By the last follow-up on 1 November 2015, with a median follow-up of 32 months, 38 relapse events and 11 deaths have occurred. Patients in the young group showed significantly lower 5-year DFS compared with their old counterparts (Fig. 1a, 62.2 vs. 77.8%, P=0.037). However, no significant difference in 5-year OS was observed between the young group and the old cohorts (Fig. 1b, 84.0 vs. 94.8%, P=0.212).Fig. 1: (a) Kaplan–Meier curves of disease-free survival (DFS) in the young group (N=74) and the elderly group (N=67); Kaplan–Meier curves of overall survival (OS) in the young group (N=74) and the elderly group (N=67).In the group of young patients, pCR was not a significant predictor for DFS (Fig. 2a, P=0.408), whereas significant differences were observed with respect to the ascending TNM stage at diagnosis (Fig. 2b, P=0.001). In the subset of old patients, neither pCR nor TNM stage was a prognostic factor against DFS (Fig. 2c, P=0.129 and Fig. 2d, P=0.174).Fig. 2: Disease-free survival (DFS) curves by chemotherapy response (a) and TNM stage at diagnosis (b) in young patients; DFS curves by chemotherapy response (c) and TNM stage at diagnosis (d) in old patients. pCR, pathological complete response.To further explore the difference in survival between young and old groups, we carried out a stratified analysis. As shown in Fig. 3, the 5-year DFS was lower in the young group than in the old group within the subgroup of patients who presented with inflammatory breast cancer [56.5 vs. 75.1%, hazard ratio (HR)=2.47, P=0.044], with a large primary tumor (46.7 vs. 81.4%, HR=2.93, P=0.053), with lymph node involvement (57.7 vs. 74.8%, HR=2.40, P=0.025), and with higher TNM stage at diagnosis (46.7 vs. 67.1%, HR=2.52, P=0.027). Subgroup analyses on OS were carried out across predefined subsets and no significant difference was observed (Fig. 4).Fig. 3: Forest plot of disease-free survival. Hazard ratio more than 1 indicated that old patients had better survival outcome. CI, confidence interval; ER, estrogen receptor; PgR, progesterone receptor; TNBC, triple-negative breast cancer.Fig. 4: Forest plot of overall survival. Hazard ratio more than 1 indicated that old patients had better survival outcome. CI, confidence interval; ER, estrogen receptor; NA, not available; PgR, progesterone receptor; TNBC, triple-negative breast cancer.Discussion Although there was no consensus definition for young breast cancer, it had been widely believed that breast cancer at a young age had a more aggressive biological behavior compared with the disease arising from older patients. Tumors in younger women present with a higher grade, a higher T stage, a higher N stage, and more dedifferentiation, and have a higher proliferating fraction and more vascular invasion 5,7–17. In our study, the clinicopathological characteristics of young patients were consistent with previous researches. Keegan et al.22 and Colleoni et al. 23 found that higher proportions of HER2-positive tumors occurred in young patients. It was reported that about 25% of all breast cancers are ER or PgR negative, but a large proportion of hormone receptor-negative tumors occur in young women 13,15,17,24. Azim et al. 11 reported that there was a significantly higher proportion of basal-like tumors (34.3%) in young patients compared with those aged 41–52 (27.7%). No significant differences in the breast cancer subtype pattern were observed in this study and this could be attributed to the limited sample size of our study. It has been shown that younger age was associated with a less favorable prognosis 5,7–17. Tang et al. 15 found that with a follow-up of 54 months, inferior 5-year DFS (72 vs. 83%, P<0.01) and 5-year OS (87 vs. 93%, P <0.01) were observed in patients aged younger than 40 years compared with those aged 40–50 years. In our study, worse 5-year DFS was observed in young patients (62.2 vs. 77.8%, P=0.037), which was consistent with the results in previous studies. Stratified analysis showed that the predictive value of age on DFS was proven in the subgroup of patients with high-risk factors, including inflammatory breast cancer, large primary tumor, positive axillary lymph node, or higher TNM tumor stage at diagnosis, whereas no difference in the 5-year DFS was observed in patients without the above-mentioned risk factors. Similarly, in the study of Han et al. 5, there was no significant difference in DFS between young and old groups in lymph node-negative patients (P=0.223), whereas the younger group showed worse prognosis among lymph node-positive patients (P<0.001). In a Korean study, patients in the very young group with lymph node metastasis had poorer 5-year OS (70 vs. 83%, P<0.001) and DFS (58 vs. 74%, P <0.001) than their older counterparts; in patients without lymph node metastasis, the survival outcomes did not differ significantly between the two groups 17. Therefore, it is a key point to identify high-risk young breast cancer patients, and implement a tailored and aggressive treatment to improve the outcomes of these patients. It had been reported that improved survival outcomes were observed in patients with pCR compared with those with residual tumor 18,25–29. Further analysis showed that pCR was associated with better DFS in ER or PgR-positive/HER2-negative with grades 1–2, HER2-positive, and triple-negative disease, but not for those with ER or PgR-positive/HER2-positive, and ER or PgR-positive/HER2-negative with grade 3 tumors 18. In addition, in a meta-regression analysis of 29 heterogeneous neoadjuvant trials, pCR was not suggested to be a surrogate end point for DFS and OS in patients with breast cancer 30. At the 2016 annual meeting of American Society of Clinical Oncology, Robidoux et al. 31 reported 5-year outcomes of the NSABP protocol B-41 and found that long-term outcomes correlated with pCR status. Additional analyses indicated that pCR was related to a significant improvement in survival rates in the ER-negative subset, but not in the ER-positive cohort. In our study, young patients achieving pCR showed similar 5-year DFS compared with those with non-pCR (P=0.408). Therefore, pCR may be not an appropriate surrogate for prognosis in young breast cancer patients treated with NCT. The TNM staging system maintained by the AJCC is considered the most clinically useful cancer staging system for cancers. Orucevic et al. 32 reported on 782 Caucasian women diagnosed with invasive ductal carcinoma who were grouped according to TNM stage and molecular phenotype. The results supported the traditional TNM staging as a continued relevant predictive tool for breast cancer outcomes even with the emerging prognostic impact of tumor biomarkers (ER/PgR/HER2). Carey et al.33 suggested that classification of residual tumor in the breast and axillary surgical specimens after NCT using the AJCC TNM staging system could predict distant relapse and survival. In our study, young patients with higher TNM stage at diagnosis showed worse survival outcomes. Therefore, TNM stage may be more predictive of prognosis than pCR in breast cancer patients treated with NCT. This study is limited by its retrospective nature, nonrandomized design, small sample size, and relatively short follow-up duration. Trastuzumab was not covered by medical insurance in China and was much more expensive than common chemotherapy drugs. Therefore, some of the HER2-positive patients could not afford the expense. The diversity of NCT regimens and difference in the proportions of patients receiving trastuzumab between young and old cohorts may also have influenced the results of this study. Further prospective studies are warranted to validate the results. In recent years, researches have confirmed that breast cancer arising in young women is a unique disease entity driven by complex biologic processes extending beyond hormone receptors and hereditary cancer syndromes. Anders et al. 34 found 367 significant gene sets among young women's tumors that specifically distinguished them from tumors arising in older women, including those related to immune function, the mammalian target of rapamycin/rapamycin pathway, hypoxia, BRCA1, stem cells, apoptosis, histone deacetylase, and multiple oncogenic signaling pathways. In the study of Azim et al. 11, breast cancer in the young was enriched with processes related to immature mammary epithelial cells and growth factor signaling. There was also downregulation of apoptosis-related genes. The identification of genomic pathways specific to breast cancer arising in young patients provided a better understanding of the interplay of age and contributing biologic processes and a unique opportunity to explore therapeutic targets. Conclusion Young breast cancer patients treated with NCT present more aggressive clinicopathological features and worse prognosis compared with their elderly counterparts. TNM stage at diagnosis may be more predictive of prognosis than pCR in young breast cancer patients with NCT. The underlying biology of young breast cancer needs to be elucidated and the development of tailored treatment is crucial. Acknowledgements The authors thank all doctors and nurses of the Department of Medical Oncology for their help with the realization of this study. Binghe Xu and Jiayu Wang designed the research, analyzed the data, and wrote the paper; Jingjing Wang analyzed the data and wrote the paper; Jiayu Wang, Qing Li, Pin Zhang, Peng Yuan, Fei Ma, Yang Luo, Ruigang Cai, Ying Fan, Shanshan Chen, Qiao Li, Binghe Xu selected the cases and analyzed the clinical data. Conflicts of interest There are no conflicts of interest.

Background: Human epidermal growth factor receptor 2 (HER2) status can undergo alteration following neoadjuvant chemotherapy (NAC) in breast cancer. This study aimed to investigate the alteration of HER2 status after NAC in breast cancer and its impact on clinical outcomes of patients, focusing on HER2-low status. Methods: We retrospectively reviewed 1,063 breast cancer patients who received NAC followed by surgery between 2013 and 2020. Using paired samples of 670 patients with residual disease, HER2 discordance rate between pre- and post-NAC samples, the relationships between HER2 discordance and clinicopathological characteristics, and clinical outcomes of the patients were analyzed. Results: As a whole, HER2-low status before NAC was associated with a lower pathological complete response rate and higher Residual Cancer Burden (RCB) class, compared with HER2-zero and HER2-positive status. However, in subgroup analysis by hormone receptor (HR) status, no statistical differences were found in chemo-responsiveness between HER2-low and HER2-zero breast cancers. Following NAC, the overall HER2 discordance rate was 21.2% (κ = 0.676). The most common type of alteration was zero-to-low (10.8%) conversion, followed by low-to-positive (3.4%) conversion. HER2 discordance was significantly associated with lower HER2 levels and HR positivity before NAC, as well as lymphovascular invasion, higher ypT stage, lymph node metastasis, and higher RCB class in residual disease after NAC. In further analyses, HER2-zero-to-low conversion showed an association with HR positivity and low histologic grade. In multivariate logistic regression analyses, HR positivity and higher RCB class were identified as independent predictive factors for HER2 discordance. In survival analyses, HER2 discordance revealed a worse prognostic impact on disease-free survival of the patients, particularly within HR-positive subgroup, which remained statistically significant on multivariate Cox regression analysis. However, no survival differences were found between patients with HER2-zero-concordant and those with zero-to-low conversion. Conclusion: Given the prognostic implications of HER2 discordance, which primarily involves zero-to-low conversion, and the therapeutic benefits of newly developed antibody-drug conjugates in HER2-low breast cancer, HER2 status should be re-evaluated in surgical resection specimens following NAC, especially in cases showing HR positivity and high RCB class. Citation Format: Hyun-Jung Sung, Hyun Jung Kwon, Hee-Chul Shin, Eun-Kyu Kim, Koung Jin Suh, Se Hyun Kim, Jee Hyun Kim, So Yeon Park. Alteration of HER2 status following neoadjuvant chemotherapy in breast cancer: a clinicopathological analysis focusing on HER2-low status [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-07-02.

The expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in residual lesions may be different compared with primary tumors of the breast after neoadjuvant therapy (NAT). Given the clinical implications of hormone receptor expression for breast cancer management, we assessed conversions in ER, PR, and HER2 in breast cancer patients after NAT. Our study comprised 589 individuals with aggressive breast cancer who underwent NAT. We examined the ER, PR, and HER2 statuses in primary and residual breast cancers and investigated the relationship between receptor conversion and clinicopathological variables. The pathologic complete response (pCR) rate for the overall cohort was 38.7%, with pCR rates of 57.0%, 13.1%, and 33.3% for HER2-positive, Luminal, and triple-negative breast cancer (TNBC), respectively. Cases with negative hormone receptor expression were more likely to achieve pCR than positive cases. The highest pCR rates were seen in HER2-positive breast cancers, followed by HER2-zero and HER2-low tumors. After NAT, there were 26 (7.8%) cases of ER status conversion and 53 (16.0%) cases of PR status conversion. The conversion of hormone receptors was mainly from positive to negative. When cases were categorized as HER2-negative or positive, 15 (5.1%) cases had a conversion of HER2 status, predominantly positive to negative. When cases were classified as HER2-zero, -low, or -positive, HER2 status conversion happened in 54 (18.6%) cases and was mostly happened between HER2-zero and HER2-low. HER2 status before NAT correlated with ER and HER2 conversion. Some breast cancer patients may show ER, PR, or HER2 status conversion after NAT. Residual lesions need to be immunohistochemically re-tested to reassess the patient's receptor expression status and to adjust the subsequent treatment regimen.

Predicting pathological completer response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer is crucial to stratify patients and individualize treatments early. Radiological information from Magnitude resonance imaging (MRI) could reflect the whole tumor content from a macroscopic scale and pathological information from biopsy whole slide images (WSIs) contain essential information about the tumor cells' living condition from a microscopic scale. However, few studies focused on predicting pCR to NAC in breast cancer by fusing radiological and pathological information. We recruited 318 patients with primary invasive breast cancer between January 2015 and December 2019 from three hospitals. The patients from Guangdong Provincial People’s Hospital (n=175) were selected as the primary cohort (PC). Others (n=143) collected from Foshan First People's Hospital (n=115) and Shantou Central Hospital (n=28) were used as external validation cohort (VC). All patients were with axial T2-weighted MRI (T2WI), diffusion-weighted imaging (DWI, b value=0 and 1000s/mm2 or 800s/mm2), and digitalized biopsy WSIs. Quantitive radiomic features were extracted from T2WI and apparent diffusion coefficients (ADC) maps derived from DWI. For pathomic features, we first tiled the WSIs with the size of 512×512 (0.25 mpp) and 256×256 (0.25 mpp) from two scales. Then we selected the tiles with the region of cells by our pretrained deep learning model. The output of the last convolution layer of the deep learning model was extracted as the patch-level features. The patch-level features were aggregated into patient-level features using bag of words (BoW) methods. We firstly investigated the predictive value of mono-omic using T2WI features, ADC features, and pathomic features separately using Light Gradient Boosting Machine (LGBM) in the PC with the reference of VC. Then we combined the T2WI, ADC, and pathomic features as multi-omics features and constructed a pCR prediction model using LGBM. Moreover, We combined multi-omics features with clinical characteristics including estrogen receptor (ER) status, progesterone receptor (PR) status, Ki67 index, and human epidermal growth factor 2 (HER2) status, tumor stage (cT), and lymph node stage (cN) for better performance. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was selected as the evaluation metric. In the mono-omic results, the model showed the lowest AUC (PC: 0.787, VC: 0.675) in the pathomic features and the highest AUC (PC: 0.989, VC: 0.725) in the T2WI modality. After fusing the three modality features as multi-omics features, the prediction performance increased compared to all mono-omic performances (PC: 0.833, VC: 0.745). Also, by adding clinical characteristics, the best performance was achieved with an AUC of 0.861 in the PC and 0.833 in the VC. The detailed AUC for each modality was shown in Table 1. Our study revealed that the pCR predictive performance of multi-omics features was better compared to mono-omic features. Although T2WI features in our study were better than the multi-omics features for pCR prediction in the PC, it suffered the overfitting problem in the VC. The multi-omics features could reflect the tumor properties from both macroscopic and microscopic scales, which could generalize the model and showed good predictive performance in all cohorts. Moreover, the predictive performance could further be boosted by combining clinical characteristics. Table 1.The AUC of the prediction of pathological complete response in the PC and VCModalityPrimary cohort(n=175)Validation cohort (n=143)T2WI0.9890.725ADC0.8560.692WSI0.7870.675Fusion0.8330.745Fusion+Clinical characteristics0.8610.833 Citation Format: Bao Li, Teng Zhu, Zhenyu Liu, Kun Wang, Jie Tian. Multi-omics fusion for prediction of response to neoadjuvant therapy in breast cancer with external validation [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 P2-12-11.

Background: Triple-negative (TN) and HER2-positive (HER2+) breast cancers have usually a worse prognosis than the luminal subtypes despite an initial chemosensitivity. The aim of this single-center study was to compare pathologic complete response (pCR) rates, disease-free (DFS) and overall (OS) survivals rates after neoadjuvant therapy according to both HER2 and hormonal status. Patients and Methods: Between 1978 and 2008, 461 patients were treated with neoadjuvant therapy at Georges-François Leclerc Cancer Center. Patients were classified in 3 groups: TN (defined by both estrogen/progesterone receptor negative and HER2 negative), HER2+ (3+ in immunohistochemistry or 2+ with amplification in fluorescence in situ hybridization) and HR+ (estrogen and/or progesterone receptor positive without HER2 overexpression or amplification). Median follow-up lasted 7.1 years [range: 0.49-29.8]. Number of events was 213 for DFS calculation and number of deaths was 150 for OS calculation. Response rates were compared using Chi2-tests. Survivals were calculated according to Kaplan-Meier and compared using log-rank tests. Univariate and multivariate Cox proportional hazards models were performed. The multivariate models were internally validated using bootstrapping (400 replications). Results: 86 of 461 were TN (19%), 125 were HER2+ (27%) and 250 were HR+ (54%). Patients with TN and HER2+ breast cancer were younger (p=0.032), had more inflammatory cancer (p=0.033) and aggressive tumors (SBR 3, P&amp;lt;0.001). Pathologic complete response rate (grades 1 and 2 of Chevallier's classification) was significantly higher for TN (22.4%) and HER2+ (29.6%) than in for HR+ (3.6%) (P&amp;lt;0.001). In univariate analysis, the following characteristics were related to a higher pCR rate: smaller clinical size (p=0.029), higher grade tumor (p=0.001) and HER2+ or TN status (P&amp;lt;0.001). In multivariate analysis, only tumor grade (p=0.022) and hormonal/HER2 status (p=0.003) were independently associated with pCR. Median DFS was 4.4years for TN, 7.8y for HER2+ and 9y for HR+ (p=0.003, logrank test). In HER2+ patients, neoadjuvant trastuzumab was associated with a higher DFS (8.65 vs. 3.24y, p=0.002). Patients who achieved a pCR had a higher DFS (p=0.015) than those with only partial pathologic response (median=6.9y vs. 12.7y). In multivariate analysis, pCR remained significant (HR (bootstrapping) = 0.5 [IC95%, 0.28-0.91], p=0.023). Median OS was 6.4y for TN, 15.1y for HER2+ and 13.1y for HR+ (P&amp;lt;0.001, logrank test). Patients who achieved a pCR had a higher OS (p=0.004) than those with non-pCR (median=not reached vs. 10.9y). In multivariate analysis, OS was lower for patients&amp;gt;50years (HR (bootstrapping)=1.79 [IC95%, 1.23-2.60], p=0.002), in TN subgroup (HR=2.46 [IC95%, 1.5-4.03], p=0.001) and when pCR was not achieved (HR=0.28, [IC95%, 0.12-0.66], p=0.003). Conclusion: After neoadjuvant therapy, TN breast cancers have a worse prognosis despite their initial chemosensitivity with a high pCR rate. HER2+ have a lower DFS than HR+/HER2- breast cancers but a better OS, mainly due to anti-HER2 targeted therapies. Pathologic complete response is a strong independent prognostic factor after neoadjuvant therapy for breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-02.

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.

The role of neoadjuvant therapy in the management of breast cancer has evolved dramatically over the past few decades. Preoperative treatment has the potential to downstage tumours and improve breast conservation rates as well as reduce the morbidity of axillary surgery. Furthermore, the in vivo sensitivity of the primary tumour to systemic therapy may be assessed at the time of final pathology when treatment is administered before operation. Monitoring of treatment response provides important prognostic and predictive information, with a pathological complete response (pCR) being associated with improved oncological outcomes1. Adjuvant therapy may also be affected in patients with residual disease who do not attain a pCR2–4. Neoadjuvant therapy for breast cancer may involve chemotherapy or endocrine therapy. The focus of this review is neoadjuvant therapy for the primary tumour in the breast. Axillary management after neoadjuvant therapy has been discussed previously5–8 and is beyond the scope of this review.

Introduction: Recently published neoadjuvant breast cancer therapy trials have documented impressive pathologic complete response (pCR) rates of up to 50% and above, depending on grade, hormone receptor and HER2 status and type of therapy. The purpose of our prospective study is to examine the predictive value of a standardized vacuum assisted core-needle biopsy (VAB) of the tumor site after neoadjuvant therapy with respect to pCR status. This is a presentation of the first case series of this single institution study. Methods: As of 2011, all patients who had completed neoadjuvant breast cancer therapy at our institution were informed about this trial regardless of their clinical response status. In case of consent, a mammography-guided VAB of the initially tagged tumor site was performed directly before the operation. In case of breast conserving surgery, mammographic wire localisation was performed immediately thereafter. Final surgery (breast conservation or mastectomy) was performed according to German guidelines. Ethical approval was obtained from the institutional review board. Pathologic complete response was defined as ypT0 ypN0. Results: Of 70 patients completing neoadjuvant therapy, 44 consented to the trial. The pCR rate was 47% (n=21). Pre-operative VAB correctly predicted residual disease in 19 of 23 cases (82,6%). We observed incorrect prediction of pathologic response if the tagging clip was not placed centrally, or if the radiologist did not perform the VAB in the tagged area. In 3 cases of pathologic partial response (pPR), all residual tumor (DCIS) was removed by VAB. In these cases, no further malignant lesions were detected in the resulting surgical specimens. Conclusions: Preliminary observations of this ongoing study are encouraging, although the correct prediction rate of residual disease is nowhere near the sensitivity needed to change clinical practice. However, if these results can be improved and confirmed in a larger series, it may be possible to reduce operative procedures after neoadjuvant therapy based on the results of a preoperative standardized VAB. Citation Format: Regina Grosse, Jana Saegenschnitter, Thi-Dao Nguyen, Susanne Unverzagt, Joerg Buchmann, Eva J Kantelhardt, Nancy Papendick, Christoph Thomssen. Vacuum assisted core-needle biopsy after neoadjuvant therapy in breast cancer to predict pathologic response [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-12.

Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) occurs in up to 20% of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers. Whether this differs among BRCA mutation carriers is uncertain. This study compared pCR between BRCA1/2 mutation carriers and matched sporadic control subjects. From November 2013 to January 2022, this study identified 522 consecutive women with clinical stage I to III HR+/HER2- breast cancer treated with NAC and surgery. The study matched BRCA1/2 mutation carriers 1:2 to non-carriers in terms of age, clinical tumor (cT) and nodal (cN) stage, and differentiation. Two-sample non-parametric tests compared baseline characteristics. Multivariable logistic regression assessed pCR (i.e., ypT0/ispN0) by BRCA1/2 mutational status. Of the 522 women (median age, 50 years), 59 had BRCA1/2 mutations, 78% of which were clinically node positive. Anthracycline-based NAC was administered to 97%. More BRCA1/2 mutation carriers were younger, had cT1 tumors, and had poorly differentiated disease. After matching, 58 BRCA1/2 mutation carriers were similar to 116 non-carriers in terms of age (p = 0.6), cT (p = 0.9), cN stage (p = 0.7), and tumor differentiation (p > 0.9). Among the mutation carriers, the pCR rate was 15.5% for BRCA1/2, 38% (8/21) for BRCA1, and 2.7% (1/37) for BRCA2 versus 7.8% (9/116) for the non-carriers (p < 0.001). After NAC, 5 (41.7%) of the 12 BRCA1 mutation carriers converted to pN0 versus 10 (37%) of the 27 BRCA2 mutation carriers and 19 (20.9%) of the 91 non-carriers (p = 0.3). In the multivariable analysis, BRCA1 mutation status was associated with higher odds of pCR than non-carrier status (odds ratio [OR] 6.31; 95% confidence interval [CI] 1.95-20.5; p = 0.002), whereas BRCA2 mutation status was not (OR 0.45; 95% CI 0.02-2.67; p = 0.5). This study showed that BRCA1 mutation carriers with HR+/HER2- breast cancers have a higher rate of pCR than sporadic cancers and may derive greater benefit from chemotherapy. The use of NAC to downstage these patients should be considered.