Stage II-III Breast Cancer Patients Research Articles

Abstract P5-05-01: Personalized Cancer Monitoring (PCM): a novel ctDNA tool to detect molecular residual disease in patients with early-stage breast cancer

Abstract Introduction: Identification of Molecular Residual Disease (MRD) in patients with breast cancer with circulating tumor DNA (ctDNA) presents a strategy to identify patients at high risk of relapse. Approaches that detect ctDNA at lower concentrations are required to increase sensitivity and improve on the lead time between ctDNA detection and clinical relapse. Here we present results using novel highly sensitive tumor-informed sequencing assays for ctDNA detection of MRD based on detection of multiple patient specific mutations in ctDNA. Methods: 62 stage II-III breast cancer patients (23 hormone receptor positive HER2 negative (HR+HER2-), 20 HER2+, 15 triple negative breast cancer (TNBC) and 4 unknown receptor status) enrolled in the ChemoNEAR sample collection study were included. All patients received neoadjuvant chemotherapy, followed up by surgery, with samples taken at diagnosis, and post-surgery every 3 months for the first two years, followed by every 6 months for up to five years. Tumor DNA from FFPE samples and germline was Whole Exome Sequenced to identify patient specific mutations and design anchored-multiplex PCR (AMP™) Personalized Cancer Monitoring (PCMTM) assays to track mutations in plasma. Cell free DNA was extracted from 613 plasma samples (median volume 4ml, range 0.5-4.5ml) and sequenced with PCMTM assays, with 37-177 variants (median 52) per panel, to a depth of 100,000x per locus. A proprietary algorithm was used to identify ctDNA. Results: At a median follow-up of 52.7 months post-surgery (range 15.3-96.4 months), ctDNA was detected in 25.8% (16/62) of patients, with detected ctDNA levels ranging from allele frequency (AF) of 0.01%, to 32.5%) (median 0.24% AF). Detection of ctDNA was associated with a high risk of future relapse (HR 65.4, 95% CI 14.5-293.7), with a median lead-time from ctDNA detection to clinical relapse of 13.7 months (range 3.9-58.9). MRD was identified in 76.9% (10/13) of patients who relapsed. ctDNA was detected prior to relapse in both patients with brain only relapse, but with a reduced lead time over clinical relapse (5.73 and 3.90 months), which was previously not achievable with digital PCR MRD-detection assays. Of patients with assessable baseline samples, 81% (39/48) had ctDNA detected. No patients with undetected ctDNA, or detectable ctDNA with AF< 0.1%, relapsed during follow-up, whereas ctDNA was detected at baseline in all 10 patients who relapsed during follow-up (p=0.1). Conclusions: PCMTM detected breast cancer relapse with a long lead-time over clinical relapse, and strong association with relapse free survival, an advancement over previously published data with digital PCR MRD detection. Prospective, interventional trials are now required to assess whether treatment on the basis of MRD detection improves outcome, including the TRAK ER Trial (NCT04985266). Citation Format: Isaac Garcia-Murillas, Giselle Walsh-Crestani, Edward Phillips, Rosalind Cutts, Sarah Hrebien, Kathryn Dunne, Kally Sidhu, Robert Daber, Amber C. Carter, Lorena De La Peña, Stephen Johnston, Alistair Ring, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Ian Smith, Nicholas Turner. Personalized Cancer Monitoring (PCM): a novel ctDNA tool to detect molecular residual disease in patients with early-stage breast cancer [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 P5-05-01.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

PurposesMost molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches.Patients and MethodsWe collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes.ResultsPAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors.ConclusionsThis is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America.Clinical Trial Registration ClinicalTrials.gov (Identifier: NCT02326857).

Đánh giá kết quả hóa trị bổ trợ phác đồ 4AC + 4 T trên bệnh nhân ung thư vú giai đoạn II, IIIA hạch nách dương tính tại Bệnh Viện Đa Khoa Tỉnh Hà Tĩnh

Objectives: (1) Evaluate the efficacy of 4AC+4T regimen as adjuvant chemotherapy for stage II, IIIA breast cancer patients with axillary lymph node positive. (2) Describe toxicity of the regimen. Methods: Retrospective and prospective descriptive longitudinal study, in 39 stage II-III breast cancer patients with lymph node positive underwent modified radical mastectomy and axillary lymph node dissection, treated with 4AC + 4T regimen at Ha Tinh General Hospital from January 2013 to June 2019. Results: Overall survival was 83.6%. Disease-free survial was 75.6%. DFS and OS are inversely proportional to tumor size, the number of metastatic lymph nodes, ER and/PR positive have a better prognosis than ER/PR negative, stage II disease have better prognosis than stage IIIA (p<0.05). Toxicities of AC+4T: Leukopenia in 64.1% of patients, with 10,1% was grade 3, 4. Neutropenia in 61.5% of patients, with 7,6% was grade 3, 4. Hypopigmentation in 51.3% of patients, with 7,6% was grade 3, 4. Thrombocytopenia in 17.9% of patients. Transaminase elevation in 43.6% of patients, no seen grade 3, 4. Increased blood creatinine was only recorded at grade 1 at 5.1%. Vomiting and nausea 87%, stomatitis 30.8%, diarrhea 38.4%, muscle pain 87%, peripheral neuropathy 74.4% peripheral edema 38.5%. Conclusion: The 4AC + 4T regimen shows high efficacy and a acceptable toxicity in the treatment of stage II, IIIA breast cancer with axillary lymph node positive.

Abstract P1-01-02: Early changes in diffuse optical tomography predicts pathologic complete response to neoadjuvant chemotherapy in triple-negative breast cancer

Abstract Background: Optical based imaging modalities have shown promise for monitoring tumor response to neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC). Patients with triple negative BC (TNBC) who achieve a pathologic complete response (pCR) have improved disease free and overall survival after NAC. In this study, we evaluated whether early changes in diffuse optical tomography breast imaging system (DOTBIS) parameters can predict a pCR. In particular, we studied total hemoglobin concentration (ctHbT) in the tumor region. Methods: This is a retrospective evaluation of 105 stage II-III BC patients enrolled in a prospective cohort study between 2011 and 2019. All patients received standard taxane-based chemotherapy in the neoadjuvant setting and pCR was defined as no invasive tumor cells from the breast and axillary tissue at surgery (ypT0 ypN0). Residual Cancer Burden (RCB) score was also calculated. By imaging the whole breast volume using low intensity near infrared light, we measured tissue concentration of oxy-hemoglobin (ctO2Hb) and deoxy-hemoglobin (ctHHb). After tumor volume segmentation, the mean ctHbT (ctO2Hb+ ctHHb) extracted from the region of interest was normalized by the non-tumor region ctHbT mean value. We conducted an independent-samples t-test to determine if there was a difference in changes in the normalized ctHbT levels at week 4 (w4) between patients with a pCR and non-pCR. A Pearson's correlation assessed for correlation between RCB score and changes in the normalized ctHbT level at w4 compared to baseline. Results: In total, 77 patients had complete data for the analysis. Of these, TNBC accounted for 18% (14/77) of BC cases. DOTBIS data was acquired at baseline for all patients. Twelve patients received weekly paclitaxel x 12, followed by dose-dense adriamycin/cyclophosphamide every 2 weeks x 4, and two received docetaxel/cyclophosphamide every 3 weeks x 6. Ten of 14 TNBC patients were imaged after four weeks of taxane-based NAC (w4). Of the 14 TNBC patients, 6 (43%) achieved pCR. Two patients were classified as RCB-I, 5 as RCB-II, and 1 non-pCR patient without an available RCB. After comparing normalized ctHbT levels at w4 to baseline, NAC was associated with an overall decrease of 28% for the pCR group (n=5) as opposed to an increase of 67% for non-pCR (n=5). The normalized ratio between ctHbT levels measured at w4 and baseline was statistically lower in the pCR group (0.72 ± 0.28) than non-pCR (1.67 ± 0.83) (95% CI, 0.17 to 2.09), p = .043. Changes in the normalized ctHbT levels after 4 weeks of NAC were strongly correlated to RCB score (r = .833, p = .005). Conclusions: This study demonstrates that changes as early as 4 weeks in DOTBIS-measured ctHbT levels in patients with TNBC receiving NAC correlate strongly with pathologic response. If further validated on a larger set, these data could potentially be used to optimize treatment outcomes or improve personalized therapeutic strategies. Citation Format: Mirella L Altoe, Kevin Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna S Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Early changes in diffuse optical tomography predicts pathologic complete response to neoadjuvant chemotherapy in triple-negative breast cancer [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 P1-01-02.

Hypofractionated postmastectomy radiotherapy with helical tomotherapy in patients with immediate breast reconstruction: dosimetric results and acute/intermediate toxicity evaluation

The aim of this study was to evaluate the dosimetry and toxicity of hypofractionation in postmastectomy radiotherapy (PMRT) with intensity-modulated radiotherapy (IMRT) in breast cancer (BC) patients. Stage II-III BC patients with implant-based immediate breast reconstruction received PMRT to the chest wall (CW) and to the infra/supraclavicular nodal region (NR) using a 15-fraction schedule (2.67Gy/fraction) and helical IMRT (Tomotherapy® System, Accuray Incorporated, Sunnyvale, CA). A score was assigned to each treatment plan in terms of planning target volume (PTV) coverage of CW and NR and the sparing of the organs at risk (OARs). The total score for each plan was calculated. Toxicity was prospectively assessed according to validated scales. Data from 120 consecutive patients treated in the period 2012-2015 were analysed with a median follow-up from the end of radiotherapy of 13.2months (range 0.0-35months). 70.8% (85/120) of the plans had high total scores as a result of an optimal coverage of both CW and RN and optimal sparing of all OARs. The maximum acute toxicity was of grade 2 in 36.7% of the cases. Early late toxicity was mild in the majority of cases. In the study population, helical tomotherapy-based IMRT produced optimal treatment plans in most cases. Acute and late toxicity was mild/moderate. Hypofractionated helical IMRT appears to be safe and feasible in the moderate term for PMRT.

The Role of Postmastectomy Radiation Therapy for Clinical Stage II-III Breast Cancer Patients With Pathological Complete Remission of Axillary Lymph Nodes After Neoadjuvant Chemotherapy

With the increasing use of neoadjuvant chemotherapy (NAC), patients with pathologically involved nodes had a great chance to be found as pathologically node negative at the time of definitive surgery. Several retrospective studies addressed that there were no survival benefits in those patient with pathologically complete remission (pCR) of axillary lymph node who treated with postmastectomy radiotherapy (PMRT) after NAC. We aim to retrospectively evaluate the role of PMRT in clinical stage II-III breast cancer patients with pathological nodes negative (ypN0) after NAC. We retrospectively identified 946 breast cancer patients with clinical stage II-III who underwent NAC in our center between 2003 and 2013. There were 290 patients achieved ypN0 after mastectomy and the clinical outcomes of the patients had been elucidated. The effects of PMRT on locoregional recurrence-free survival (LRRFS), disease-free survival (DFS) and overall survival (OS) were evaluated by Kaplan-Meier method and compared using the log-rank test. Prognostic factors associated with survival were evaluated by univariate and multivariate analysis. The median age was 50 years old (range, 25-80 years). All patients received 2-8 cycles (median, 4 cycles) of preoperative chemotherapy contained with anthracycling and paclitaxel and mastectomy. Of the 290 patients, 217 (74.8%) underwent PMRT and 73 (25.2%) did not. With a median follow-up time of 63 month, 12 patients developed LRR and 39 developed distant metastasis. The 5-year LRRFS, DFS and OS was 94.2%, 79.3% and 91.8% in no-PMRT group and 95.9%, 84.3% and 92.4% in PMRT group, respectively (p=NS). There was no significant difference between the patients with PMRT and without PMRT in terms of survival outcome, even for the subgroup of patients with clinical stage III disease or with residual disease in breast after NAC. On univariate and multivariate analysis, there were no benefits of PMRT on LRRFS (hazard ratio [HR], 0.714; 95% confidence interval [CI], 0.193-2,634; p =0.612), DFS (HR 0.908; 95%[CI], 0.477-1.734; p = 0.773) or OS (HR, 0.829; 95% [CI], 0.291-2.359; p =0.725). Age at diagnosis，ER and LVI status, adjuvant chemotherapy were independent prognostic factors for LRRFS （p＜0.01）, primary tumor response to NAC was marginally significant with poor LRRFS (hazard ratio [HR] 0.109; 95% CI, 0.011-1.098; p=0.06). Advanced Clinical T stage (T3-T4) was independently associated with decreased DFS and OS. Patients who achieved ypN0 after NAC without PMRT had similar outcomes compared with patients treated with PMRT, regardless of clinical stage and primary tumor response. PMRT might not be necessary for ypN0 patients. Prospective randomized study is needed to identify whether it is safe to omit PMRT in patients with clinical stage II-III disease and achieved ypN0 after NAC and mastectomy

Abstract P1-14-09: Long term survival of locally advanced breast cancers (LABC) treated with neoadjuvant treatment, results of a multicenter randomised phase II study (Remagus 02 trial)

Abstract Backgound : The primary analysis of the REMAGUS-02 multicenter randomized phase II trial demonstrated that celecoxib did not improve pCR rates in pts with HER2-negative localized invasive breast cancer (BC), whereas trastuzumab increased pCR rates in HER2-positive ones [Pierga BCRT 2010]. We report here the long-term follow-up results of this trial for disease free survival (DFS) and overall survival (OS). Patients and methods: From May 2004 to October 2007, 340 stage II-III BC patients were randomly assigned to receive 4 cycles (c) of epirubicin–cyclophosphamide q 3 w followed by 4 c of docetaxel q 3 w +/- trastuzumab in HER2 positive pts (120 pts) or +/- celecoxib in HER2 negative pts (n=220). From September 2005, all pts with HER2 positive BC received adjuvant T for a total of 18 c (n=106). Patients with hormone receptors (HR) positive tumor received adjuvant endocrine treatment according to menopausal status Results: With a median follow up of nearly 8 years (94.4 months, 20-127m), 112 relapses and 75 deaths have been observed (median DFS and OS not reached). Eight years DFS and OS were respectively 63 % [57%-71%] and 75 % [70%-81%] in HER2 negative group; and 75% [67%-83%] and 82 % [74%-90%] in HER2 positive group. DFS was significantly higher in HER+ pts than in HER2-(HR: 0.64 [0.42-0.99], p=0.042), whereas OS did not differ significantly (HR: 0.67, [0.41-1.11], p=0.123). In the overall population, progesterone receptor (PgR) positivity was associated with a better DFS (p=0.012) and OS (p<0.001) as compared to ER+/PgR- (DFS: HR=2.07 [1.27-3.39]; OS: HR=2.53 [1.3-4.92]) and ER-/PR-; DFS: HR=1.56 [0.98-2.46]; OS: HR: 3.34 [1.87 – 5.97]. In the ER-/PR- group, DFS reached a "plateau" after three years follow-up, while the annual risk of relapse remained constant in the ER+/PR- subgroup. In the HER2- subgroup, no effect of neoadjuvant celocoxib was observed on survival, neither in intention to treat (ITT) nor in per protocol analyses. In the multivariate analysis clinical stage (T3/T4 versus T2, HR: 1.92 [1.209 - 3.05], p=0.006), PgR status (positive versus negative HR : 0.52, [0.32-0.84], p=0.007) and pCR (yes vs no, HR : 0.213 [0.066-0.687], p=0.01) were significant predictors of DFS. In the HER2+ subgroup, neoadjuvant versus adjuvant trastuzumab was not significantly associated with DFS, neither in the ITT, nor in the per protocol analysis. Conclusion: Celecoxib was not associated with pCR or survival benefit when added to conventional neoadjuvant CT in Her2-negative BC pts. Lack of PgR expression is a major prognostic factor for survival. Neoadjuvant versus adjuvant trastuzumab increased pCR rates but did not change significantly DFS and OS of HER2 positive BC pts. Citation Format: Giacchetti S, Hamy-Petit A-S, Delaloge S, Brain E, Berger F, Mathieu M-C, de Cremoux P, Bertheau P, Guinebretière J-M, Saghatchian M, Tembo O, Marty M, Pierga J-Y. Long term survival of locally advanced breast cancers (LABC) treated with neoadjuvant treatment, results of a multicenter randomised phase II study (Remagus 02 trial). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-09.

Abstract P3-06-12: Estimating prevalence of stage II-III breast cancer in the United States by treatment and biologic subtypes using oncology clinic data

Abstract Background: Breast cancer (BC) is the most common malignancy and the second most common cause of cancer death among women in the US, and the main cause of death in women ages 40 to 49 years. Stage II and III BC are diverse diseases represented by several biologic subtypes with distinct behaviors, which have not been quantified outside of clinical trials or SEER using observational data. Additionally, although guidelines address the use of adjuvant treatment (tx) based on tumor grade, lymph node involvement, tumor size, and whether the tumor expression pattern is consistent with estrogen receptor (ER), progesterone receptor (PR), or Her2 receptor over-expression, there is considerable heterogeneity in clinical practice with respect to the types of tx used for patients with early stage BC. The objective of this study was to estimate the number of women (prevalence) with Stage II and III BC in the US by year, as well as the proportion of patients treated with chemotherapy or biologic tx, stratified by subtype and age using electronic medical record (EMR) data from oncology clinics. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database was used to identify women with early stage BC and ≥1 visit to a clinic in each year, 2009-2012. OSCER captures EMR data on >500,000 cancer patients since 2004 from outpatient community and hospital-affiliated oncology practices across the US. Women with a diagnosis of BC (ICD-9 174) were identified using a 4-year look-back period. Women with stage I disease were excluded due to variability in the use of adjuvant tx. Treated patients were defined as receiving any chemotherapy or biologic tx during the year of interest. Raw counts from OSCER were projected nationally with 95% confidence intervals through direct estimation methods utilizing claims data. Results: When projected to the US population, the prevalence of women with Stage II or III BC was estimated at 316,827 (311,040 - 322,614), 308,792 (303,267 - 314,317), 317,691 (311,543 - 323,839), and 321,281 (315,470 - 327,092) from 2009-2012, respectively. In 2012, 65% of these women had Stage II disease, 76% were over the age of 50, 30% were Her2 positive (+ve), and 63% were ER/PR +ve (17% were Her2/ER/PR +ve). Approximately 46% of Stage II-III BC patients received treatment in an outpatient oncology clinic (45% of Stage II and 48% of Stage III). The proportion of early-stage BC patients receiving tx was very similar across biologic subtypes. Women 65 years or older were least likely to receive tx (42%) of all strata examined. 2012 Patients Prevalence% treatedBC Stage II-III32128146Stage II20932745Stage III11195448Her2 Status Her2 +ve9677451Her2 -ve22450744ER, PR Status ER, PR +ve20328644ER -ve, PR +ve498952ER +ve, PR -ve3339145ER, PR -ve7961552Age Group <507608152≥5024520045<6521016948≥6511111242 Conclusions: This is the first study to estimate diagnosed and treated prevalence of women with Stage II or III BC by hormonal and Her2 status in the US using real-world EMR data. These data suggest that adjuvant chemotherapy or biologic tx is used in approximately 46% of women after BC diagnosis, and women age 65 years or older are less likely to receive adjuvant tx. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-12.

The Role of Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy in Clinical Stage II-III Breast Cancer Patients With pN0: A Multicenter, Retrospective Study (KROG 12-05)

The purpose of this study was to investigate the role of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy (NAC) in clinical stage II-III breast cancer patients with pN0. We retrospectively identified 417 clinical stage II-III breast cancer patients who achieved an ypN0 at surgery after receiving NAC between 1998 and 2009. Of these, 151 patients underwent mastectomy after NAC. The effect of PMRT on disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and overall survival (OS) was evaluated by multivariate analysis including known prognostic factors using the Kaplan-Meier method and compared using the log-rank test and Cox proportional regression analysis. Of the 151 patients who underwent mastectomy, 105 (69.5%) received PMRT and 46 patients (30.5%) did not. At a median follow-up of 59 months, 5 patients (3.3%) developed LRR (8 sites of recurrence) and 14 patients (9.3%) developed distant metastasis. The 5-year DFS, LRRFS, and OS rates were 91.2, 98.1, and 93.3% with PMRT and 83.0%, 92.3%, and 89.9% without PMRT, respectively (all P values not significant). By univariate analysis, only age (≤40 vs >40 years) was significantly associated with decreased DFS (P=.027). By multivariate analysis, age (≤40 vs >40 years) and pathologic T stage (0-is vs 1 vs 2-4) were significant prognostic factors affecting DFS (hazard ratio [HR] 0.353, 95% confidence interval [CI] 0.135-0.928, P=.035; HR 2.223, 95% CI 1.074-4.604, P=.031, respectively). PMRT showed no correlation with a difference in DFS, LRRFS, or OS by multivariate analysis. PMRT might not be necessary for pN0 patients after NAC, regardless of clinical stage. Prospective randomized clinical trial data are needed to assess whether PMRT can be safely omitted in pN0 patients after NAC and mastectomy for clinical stage II-III breast cancer.

The Role of Postmastectomy Radiation Therapy (PMRT) in Clinical Stage II-III Breast Cancer Patients With pN0 After Neoadjuvant Chemotherapy: A Multicenter, Retrospective Study (KROG 12-05)

The Role of Postmastectomy Radiation Therapy (PMRT) in Clinical Stage II-III Breast Cancer Patients With pN0 After Neoadjuvant Chemotherapy: A Multicenter, Retrospective Study (KROG 12-05) S. Shim, P. Won, H. Seong Jae, S. Kyung Hwan, S. Chang Ok, K. Su Ssan, S. Hyun Soo, K. Ki Chang, K. Jin Hee, and L. Hyung-Sik; Department of Radiation Oncology, Eulji Medical Center, Eulji University School of Medicine, Daejeon, Korea, Republic of Korea, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of Korea, 3Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goynag, Korea, Republic of Korea, Department of Radiation Oncology, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of Korea, Department of Radiation Oncology, Asan Medical Center, University of Ulsan, Seoul, Korea, Republic of Korea, Department of Radiation Oncology, Bundang CHA Hospital, School of Medicine, CHA University, Seongnam, Korea, Republic of Korea, Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of Korea, Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea, Republic of Korea, Department of Radiation Oncology, Dong-A University Hospital, Dong-A University School of Medicine, Busan, Korea, Republic of Korea

Is Elective Nodal Irradiation Necessary in Patients With Negative Pathologic Lymph Node Status After Neoadjuvant Chemotherapy Followed by Breast Conserving Surgery for Clinically Stage II-III Breast Cancer?: A Multicenter Retrospective Study (KROG 12-05)

To evaluate the effect of elective nodal irradiation (ENI) in clinically stage II-III breast cancer patients with pathologically negative lymph node (ypN0) after neoadjuvant chemotherapy (NAC) followed by breast conserving surgery (BCS) and radiation therapy (RT).

Abstract P1-14-03: Overall survival results of a multicenter randomized phase II study in locally advanced breast cancer patients treated with or without neoadjuvant Trastuzumab for HER2 positive tumor (Remagus 02 trial)

Abstract Background: Trastuzumab is indicated in neoadjuvant setting in locally advanced HER2 positive breast cancer patients (Gianni L. Lancet 2010). There is no data on the impact of the use of neoadjuvant Trastuzumab (T) compared to adjuvant T on survival. Patients and methods: From May 2004 to October 2007, 341 stage II-III breast cancer patients were included in a phase II randomized trial and received 4 cycles (c) of epirubicin (75 mg/m2 d1)–cyclophosphamide (750 mg/m2 d1) q 3 w followed by 4 (c) of docetaxel (100 mg/m2 d1) q 3 w. Pts with HER2+++ tumor (120 pts) were randomized to receive or not neoadjuvant T combined with docetaxel. From September 2005, all pts with HER2+cancer received adjuvant T for a total of 18 c (106 pts). All pts with hormone receptors positive tumor received hormonal treatment according to menopausal status (Pierga et al BCRT 2010). We report here overall survival (OS) and disease free survival (DFS) data at 5 year and associated prognostic factors. Results: At a median follow up of 49 months, the median DFS was not reached for the whole population and was statistically superior for the HER2 positive cancer patients treated with chemotherapy plus neoadjuvant T compared to the other groups, p = 0.018. The median OS is not reached for the whole population and is statistically higher in HER2 positive tumor group compared to HER2 negative group (p = 0.00077). For 106 HER2 positive breast cancer patients who had received one year of complete trastuzumab treatment, there was no significant difference in OS and DFS between pts who started T in neoadjuvant setting versus in adjuvant setting. DFS and OS were not significantly influenced by pathological Complete Response rate (pCR) (respectively, p = 0.22 and p = 0.56). At multivariate analysis including 6 factors (age, tumor size, clinical lymph node, ER, PgR), factors which influenced OS were tumor size (p = 0.03) and ER expression (p = 0.06) and for DFS, clinical lymph node status (p = 0.049) and PgR expression (p = 0.046). Conclusion: pCR is not a surrogate of survival in the HER2+subgroup. HER2 positive breast cancer pts receiving trastuzumab have a significant higher OS than those with HER2 negative tumors. OS and DFS do not seem to differ between the neoadjuvant T group and the T adjuvant group. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-03.

Abstract P1-14-18: Overall survival results of a multicenter randomized phase II study in locally advanced breast cancer patients treated with or without celecoxib for HER2 negative tumor (Remagus 02 trial)

Abstract Background: Cox 2 is frequently over expressed in breast cancers. Celecoxib is a COX-2 inhibitor with anti angiogenic and pro-apoptotic activities. There are few data of anti-COX2 treatment in breast cancers. and no data on the impact of neoadjuvant anti COX 2 agent on survival. Patients and methods/: From May 2004 to October 2007, 340 stage II-III breast cancer patients were included in a phase II randomized trial and received 4 cycles (c) of epirubicin (75 mg/m2)–cyclophosphamide (750 mg/m2) q 3 w followed by 4 (c) of docetaxel (100 mg/m2) q 3 w. Pts with HER2 negative tumors (220 pts) were randomized to receive or not neoadjuvant celecoxib (200 mg bid) combined with docetaxel. All pts with hormone receptors positive tumor received hormonal treatment according to menopausal status (Pierga et al BCRT 2010). We report here overall survival (OS) and disease free survival (DFS) data and prognostic factors analyses at 5 years. Results/: At a median follow up of 49 months, the median DFS and OS are not reached for the whole population and none of them is significantly different between pts who received celecoxib or who did not (p = respectively 0.62 and 0.36). Celecoxib had no impact either on clinical and pathological complete response rate (pCR). DFS is significantly higher in patients who achieved pCR as compared to those who did not (p = 0.017; RR = 0.21 [0.051–0.88], whereas OS is borderline significant [p = 0.07; RR = 0.19 (0.026–1.4)]. Patients with triple negative (TN) tumors (78 pts) achieved worst DFS (p = 0.02) and OS (p <0.001) than non triple negative ones despite their higher pCR rate, 29.5 % [95 % CI 19;7-40;9 %] vs 11.4 % in all the other subgroups. At multivariate analysis including 7 factors [tumor size, clinical lymph node, grade (1 vs. 2and 3), pCR, ER, PR, TN], factors which influenced OS and DFS were pCR (p = 0.034 & 0.013 and PgR expression (p = 0.046 & 0.01). Conclusion/: Celecoxib had no influence on pCR, DFS or OS. Despite higher pCR rate triple negative breast cancer patients' subgroup remains with the poorest outcome. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-18.

Abstract P5-04-01: Expression of epithelial-mesenchymal transition (EMT)-related markers in primary tumors and matched lymph node metastases in breast cancer patients

Abstract Background. Malignant tumors may include multiple cancer cell populations with various metastatic potential. More aggressive subpopulations might easier be captured in lymph nodes metastases (LNM) than in primary tumors (PT). We evaluated mRNA and protein levels of master EMT regulators: TWIST1, SNAIL and SLUG, protein levels of EMT-related markers: E-cadherin, vimentin, and expression of classical breast cancer receptors: HER2, ER and PR in PT and corresponding LNM. The results were correlated with clinicopathological data and patient outcomes. Methods. Formalin-fixed paraffin-embedded (FFPE) samples from PT and matched LNM from 42 stage II-III breast cancer patients were examined. Expression of TWIST1, SNAIL and SLUG was measured by RT-qPCR, with median as cut off for positive result. Protein expression was examined by immunohistochemistry on tissue microarrays. For TWIST1, SNAIL, SLUG, E-cadherin and vimentin >10% of positively stained cells defined positive result. ER and PR were scored according to Allred system, and HER2 - according to HercepTest criteria. Results were considered concordant if PT and LNM were both positive or both negative. Concordance was measured by estimating Cohen's kappa coefficient (κ), with κ value equal 1 indicating perfect agreement. Disease-free survival (DFS) and overall survival (OS) were compared using F-Cox test. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were computed using Cox regression analysis. Results. On average, expression of TWIST1, SNAIL and SLUG was significantly higher in LNM compared to PT (P < 0.00001 for all). Gene and protein levels of TWIST1, SNAIL and SLUG were highly discordant between PT and matched LNM (Tab 1). Receptor conversion, particularly loss of ER and PgR, occurred in 18% and 29% of cases, respectively. Increased expression of TWIST1 and SNAIL in LNM was associated with shorter OS (p = 0.045 and p = 0.022, respectively) and DFS (p = 0.02 and p = 0.01, respectively), whereas their expression in PT had no prognostic impact. Negative-to-positive switch of TWIST, SNAIL and vimentin correlated with shorter OS and DFS. Conversion of ER and PR had no significant impact on survival. Conclusions. LNM are enriched in cells with more aggressive phenotype, marked by elevated levels of EMT regulators. High expression of TWIST1 and SNAIL in LNM, as well as negative-to-positive conversion of both TWIST1 and SNAIL confer worse prognosis, confirming the correlation of EMT with aggressive disease behavior. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-04-01.

Expression of epithelial to mesenchymal transition-related markers in lymph node metastases as a surrogate for primary tumor metastatic potential in breast cancer

BackgroundBreast cancers are phenotypically and genotypically heterogeneous tumors containing multiple cancer cell populations with various metastatic potential. Aggressive tumor cell subpopulations might more easily be captured in lymph nodes metastases (LNM) than in primary tumors (PT). We evaluated mRNA and protein levels of master EMT regulators: TWIST1, SNAIL and SLUG, protein levels of EMT-related markers: E-cadherin, vimentin, and expression of classical breast cancer receptors: HER2, ER and PgR in PT and corresponding LNM. The results were correlated with clinicopathological data and patients outcomes.MethodsFormalin-fixed paraffin-embedded samples from PT and matched LNM from 42 stage II-III breast cancer patients were examined. Expression of TWIST1, SNAIL and SLUG was measured by reverse-transcription quantitative PCR. Protein expression was examined by immunohistochemistry on tissue microarrays. Kaplan-Meier curves for disease-free survival (DFS) and overall survival (OS) were compared using F-Cox test. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were computed using Cox regression analysis.ResultsOn average, mRNA expression of TWIST1, SNAIL and SLUG was significantly higher in LNM compared to PT (P < 0.00001 for all). Gene and protein levels of TWIST1, SNAIL and SLUG were highly discordant between PT and matched LNM. Increased mRNA expression of TWIST1 and SNAIL in LNM was associated with shorter OS (P = 0.04 and P = 0.02, respectively) and DFS (P = 0.02 and P = 0.01, respectively), whereas their expression in PT had no prognostic impact. Negative-to-positive switch of SNAIL protein correlated with decreased OS and DFS (HR = 4.6; 1.1-18.7; P = 0.03 and HR = 3.8; 1.0-48.7; P = 0.05, respectively).ConclusionsLNM are enriched in cells with more aggressive phenotype, marked by elevated levels of EMT regulators. High expression of TWIST1 and SNAIL in LNM, as well as negative-to-positive conversion of SNAIL confer worse prognosis, confirming the correlation of EMT with aggressive disease behavior. Thus, molecular profiling of LNM may be used as surrogate marker for aggressiveness and metastatic potential of PT.

Prognostic Value of a Positive-to-negative Change in Hormone Receptor Status after Neoadjuvant Chemotherapy in Patients with Hormone Receptor–positive Breast Cancer

To investigate the prognostic value of positive-to-negative changes in hormone receptor (HR) status after neoadjuvant chemotherapy (NCT) in patients with HR-positive breast cancer. Data from 224 stage II-III breast cancer patients with positive HR status before NCT who had residual disease in the breast after NCT were collected. HR status of the residual tumors was retested after NCT. A survival analysis was performed in 214 patients with adjuvant endocrine therapy regardless of post-NCT HR status. The survival analysis also examined other clinical and pathologic variables. In total, 15.2 % of patients had a positive-to-negative change in HR status after NCT, and this change was observed more frequently in HER-2-positive tumors than HER-2-negative tumors (P = 0.001). In 214 patients who had been treated with adjuvant endocrine therapy regardless of post-NCT HR status, the alteration in HR status was an independent factor for the prediction of a poorer disease-free survival (P = 0.026) and overall survival (P < 0.001) in the adjuvant endocrine therapy patients. The 5-year disease-free survival and overall survival rates were 43.5 % and 59.8 %, respectively, in patients with HR status conversion and 67.8 % and 82.5 %, respectively, in patients whose HR status remained positive (log rank test P = 0.003 and P = 0.001). The switch of HR status after NCT is remarkable for HR-positive tumors. An HR-negative switch may identify patients who would benefit from alternative systemic therapies.

De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer

BackgroundMicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome.MethodsThe pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers.ResultsMore than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients.ConclusionsOur study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.

P2-12-18: A Prognostic Model Based on Node Status, Cathpesin-D and Ki-67 Predict the Outcome of Patients Failing To Achieve Pathological Complete Response after Anthracycline-Based Neoadjuvant Chemotherapy for Breast Cancer.

Abstract Background Aim of this study was to evaluate factors which could possibly affect the outcome of patients failing to achieve pathological complete response (pCR) after anthracycline-based neoadjuvant chemotherapy (NCT) for breast cancer, and built a prognostic model to predict disease free survival (DFS) and overall survival (OS). Material and Methods: We retrospectively collected data of 199 stage II-III breast cancer patients who had failed to achieve pathological complete response after neoadjuvant chemotherapy in Shanghai Cancer Hospital. The NCT regimens were NE (navelbine 25mg/m2, day 1, 8 and epirubicin 60mg/m2, day 1; every three weeks) or CEF (cyclophosphamide 600 mg/m2, day 1; epirubicin 60 mg/m2, day 1 and 5-fluorouracil 600 mg/m2, day 1; every three weeks) for a median treatment course of 3 cycles. To develop the prognostic model, variables at baseline(age, menopausal status, tumor size, node status, ER, PR, and HER-2) and at surgery(tumor size, grade, histotype, node status, vascular invasion, ER, PR, HER-2, Cathpesin-D, P53, Topo-IIα, Nm-23, Bcl-2, BAX, MDR, GSTn, PS2, P27, Cyclin D1 and Ki-67) were investigated. Multivariate Cox regression model and Kaplan-Meier method was used to build the model, and show the discrimination of DFS and OS in different risk groups. Results: By multivariate analysis, ≥4 lymph node metastasis (HR=1.9, P=0.009), Cath-D positive (HR=2.5, P=0.006), and Ki-67 index≥20% (HR=1.9, P=0.001) at surgery were independent predictors for lower DFS and OS rate among non-pCR responders. We built a prognostic scoring model on the basis of these variables, in which ≥4+ nodes, Cath-D + or Ki-67 index≥20% would contribute 1 point separately to the risk score. The 5-year DFS rates in low(0 point), intermediate-low(1 point), intermediate-high(2 points) and high risk groups(3 points) were 94%, 65%, 43%, and 28%, respectively (Log-rank teat p&amp;lt;0.001). The 5-year OS rates in these four groups were 94%, 84%, 66% and 34%, respectively (Log-rank test p&amp;lt;0.001). Conclusion: Post-NCT node status, Cathpesin-D and Ki-67 were used to develop a prognostic model which could simply discriminate patients with poor prognosis among non-pCR responders after anthracycline-based neoadjuvant chemotherapy, and might help to tailor further individualized treatment strategies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-18.

P2-14-01: Race, Response to Chemotherapy, and Outcome within Clinical Breast Cancer Subtypes.

Abstract Introduction: Racial disparity in breast cancer (BC) outcome has been attributed to access to care, socioeconomic factors, and biologic factors. In particular, the prevalence of triple negative BC is significantly higher among African-American (AA) women than white women (non-AA). However a recent population-based study suggests that racial disparities persist even if stratified by subtype, although it is possible that bias in stage at presentation may have influenced these results. In this study, we examined 464 women of uniform clinical stage II-III breast cancer, all treated with neoadjuvant chemotherapy, and examined pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS) to see if racial disparity exists within a more homogeneous stage and treatment cohort. Methods: The UNC Neoadjuvant Breast Cancer Database is a prospectively maintained cohort with clinical and outcome annotation. We identified women diagnosed between 1991–2011 and assigned BC subtype by clinical assay for estrogen receptor and progesterone receptor (hormone receptors, HR) and HER2. Fisher's Exact and Wilcoxon Rank sum tests compared characteristics between AA and non-AA. The Kaplan-Meier method and Log Rank test compared OS and RFS curves. Results: 142 (31%) of 464 women were AA, 294 (63%) were white, and 28 (6%) were other races (for analysis white and “other” were categorized as non-AA). 191 (41%) were clinical stage II and 273 (59%) stage III at diagnosis. Stage at diagnosis did not differ between AA and non-AA (p=0.07). AA were slightly older (median age 49 v 45, p=0.01) and were more likely to be HR-/Her2- (44% v 25%, p=0.003). All patients received preoperative chemotherapy. AA received less biologic therapy such as trastuzumab or on-protocol bevacizumab (10% v 18%, p=0.03) and received significantly less endocrine therapy (46% v 59%, p=0.01) than non-AA patients. 102 (22%) of patients had a pCR to neoadjuvant chemotherapy; pCR rates did not differ significantly by race (p=0.7) or within subtype by race (all p&amp;gt;0.14). At a median follow-up of 4.5 years, 121 (26%) of patients have died. Among HR-/HER2− (n=114) and HR-/HER2+(n=47) patients, OS and RFS did not differ between AA and non-AA (all p&amp;gt;0.5). Conversely, among HR+/HER2− patients (n=159) AA had worse OS (p=0.01) and RFS (p= 0.03) and among HR+/HER2+ patients (n=53), AA had worse OS (p=0.0004) and RFS (p=0.005). Conclusion: In this cohort of clinical stage II-III BC patients, AA women were over 75% more likely to have triple negative BC than non-AA patients. Pathologic reponse to chemotherapy did not differ between AA and non-AA patients. Examining the entire cohort, AA women had worse RFS and OS, however there was no difference among ER-negative subtypes. The difference in RFS and OS was driven by worse outcome among women with ER or PR+ tumors (regardless of HER2). It is possible that this racial disparity in outcome among hormone receptor-positive BC patients reflects unknown biologic differences by race, or differences in access to or receipt of endocrine therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-01.

Postmastectomy Radiation Therapy in Stage II-III Breast Cancer Patients

Postmastectomy Radiation Therapy in Stage II-III Breast Cancer Patients <35 Years Old Treated with Doxorubicin-based Neoadjuvant Chemotherapy and Mastectomy