Primary Operable Breast Cancer Patients Research Articles

Influence of alcohol sensitivity on bone metastases and skeletal-related events in primary operable breast cancer: A retrospective cohort study.

BackgroundBone metastases in breast cancer patients are a common concern for medical doctors and dentists. Bone-modifying agents, which are necessary to prevent skeletal-related events (SREs), are associated with osteonecrosis of the jaw as an adverse side effect. Hypersensitivity to alcohol is an unfavorable response caused by deficiency of aldehyde dehydrogenase-2 (ALDH2) activity. Inactive ALDH2 is associated with osteoporosis, but its influence on bone metastases is unclear. The aim of our study was to evaluate the effects of alcohol sensitivity on bone metastases and SREs in primary operable breast cancer patients.MethodsWe retrospectively analyzed patients who were administered docetaxel, an anti-tumor agent, for histologically diagnosed breast cancer between April 2004 and September 2015. Alcohol sensitivity was assessed based on medical records of hypersensitivity to alcohol. The primary endpoint was time to bone metastases and the secondary endpoint was time to first SRE from the initial docetaxel administration. Data were stratified by alcohol sensitivity and tumor stages, and differences were estimated by the Kaplan-Meier method. Prognostic risk factors were analyzed by the multivariate Cox proportional hazards model.ResultsThe median follow-up period of patients with high sensitivity to alcohol (n = 45) was 54 months and that for those with low sensitivity (n = 287) was 64 months. Stratification by alcohol sensitivity revealed that tumor stage exhibited significant correlations with the cumulative incidence of bone metastases in low-sensitivity patients; however, no differences were found in high-sensitivity patients. In multivariate analysis, alcohol sensitivity was a significant prognostic risk factor for bone metastases (HR 2.721, 95% CI 1.268–5.841, P = 0.010).ConclusionAlcohol sensitivity may be a prognostic risk factor for bone metastases. More detailed genetic investigations and metabolic analyses are needed.

Oncologic Outcome of Endoscopic Assisted Breast Surgery Compared with Conventional Approach in Breast Cancer: An Analysis of 3426 Primary Operable Breast Cancer Patients from Single Institute with and Without Propensity Score Matching

Endoscopy-assisted breast surgery (EABS) performed through minimal axillary and/or peri-areolar incisions is a possible alternative to conventional breast surgery (CBS) for certain patients with breast cancer. In this study, we report the oncologic safety results of EABS compared with CBS. Patients underwent EABS for breast cancer during the period June 2010 to March 2020 were collected from the EABS database from single institute, and another cohort of patients, who received CBS, were identified to determine the effectiveness and oncologic safety of EABS. A case-control study was conducted using propensity score matching (PSM) to prevent bias from cases selection. A total of 3426 patients were enrolled in the current study, including 405 patients receiving EABS and 3021 underwent CBS. Before PSM, patients selected for EABS tend to be smaller in tumor size, node negative, early stage, low histologic grade, and HER-2 negative. After PSM, 343 patients underwent EABS were compared with another 343 patients received CBS. The margin involved rate in EABS group is 2.6%, and 5.6% in CBS group (p = 0.054) after PSM. In breast conserving cases, the margin involved rates were 2% in EABS group, and 7.2% in CBS group (p = 0.04). In Kaplan-Meier survival curves analysis, there was no difference in local regional recurrence (p = 0.89), distant metastasis (p = 0.08), and overall survival (p = 0.14). The preliminary oncologic safety analysis from current study showed EABS is a safe procedure and results in low margin involved rate, and no increase of locoregional recurrence, distant metastasis or mortality compared with CBS.

ASO Visual Abstract: Oncologic Outcome of Endoscopic-Assisted Breast Surgery Compared with Conventional Approach in Breast Cancer: An Analysis of 3426 Primary Operable Breast Cancer Patients from a Single Institute With and Without Propensity Score Matching

ASO Visual Abstract: Oncologic Outcome of Endoscopic-Assisted Breast Surgery Compared with Conventional Approach in Breast Cancer: An Analysis of 3426 Primary Operable Breast Cancer Patients from a Single Institute With and Without Propensity Score Matching

Abstract 198: Molecular genetic characterization of primary breast cancer via clinical next-generation sequencing

Abstract Targeting appropriate driver genes is crucial in cancer precision medicine. To find oncogenic drivers, targeted next-generation sequencing is becoming widely used in the clinical field. Using targeted next-generation sequencing, we aimed to detect targetable genetic alterations and characterize mutational profiles of breast cancer. We analyzed breast cancer biopsy specimens using customized 50-gene panel. In total, 196 patients of primary operable breast cancer patients were selected from single institution in South Korea. Among the 196 patients, 22 kinds of genes were significantly mutated or amplified. They comprised 161 nonsynonymous missense mutations, 54 frameshift mutations, 29 missense mutations and 5 small indels; 64 gene amplifications and 2 deletions. The most frequently mutated gene was PIK3CA (n=81/196; 41.3%), followed by TP53 (n=62; 31.6%), AKT1 (n=21; 10.7%), GATA3 (n=17; 8.7%) and PTEN (n=14; 7.1%). The most frequently amplified gene was ERBB2 (n=25/196; 12.8%), followed by FGFR1 (n=11; 5.6%), MYC (n=9; 4.6%), FGFR2 (n=3; 1.5%) and FGFR3 (n=3; 1.5%). Targeted next-generation sequencing can be readily performed in daily clinical practice. The most commonly found targetable genetic alterations were mutations of PI3K/AKT/mTOR pathway genes and FGFR family gene amplifications. Despite the limited number of available targeted agents, our study shows the feasible application of precision medicine in breast cancer. Citation Format: Jung Ho Park, Seung Yeon Ko, Sang Hwa Kim, Ho Young Kim, Sung Hoon Ko, Lee Su Kim. Molecular genetic characterization of primary breast cancer via clinical next-generation sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 198.

A new clinical-genomic model to predict 10-year recurrence risk in primary operable breast cancer patients

This study aimed to validate the long-term prognostic value of a new clinical-genomic model, Distant Genetic Model-Clinical Variable Model 6 (DGM-CM6), developed in Asia as a prognostic panel for all subtypes of breast cancer. We included 752 operable stage I–III breast cancer patients representing all subtypes treated from 2005 to 2014 as the validation cohort. The median follow-up was 95.8 months. The low- and high-risk patients classified by DGM-CM6 (RI-DR) had significant differences in 10-year distant recurrence-free interval (DRFI) (94.1% vs. 85.0%, P < 0.0001) and relapse-free survival (RFS) (90.0% vs. 80.5%, P = 0.0003). External validation using EMTAB-365 dataset showed similar observation (P < 0.0001). DGM-CM6 was an independent prognostic factor by multivariate analysis with hazard ratios of 3.1 (1.6–6.0) for RFS (P = 0.0009) and 3.8 (1.6–9.0) for DRFI (P = 0.0028). Comparing the C-index of DGM-CM6 and PAM50-ROR scores, the former performed better than the latter in predicting long-term DRFI and RFS, especially in N0, ER/PR-positive, and HER2-negative patients.

Abstract P4-02-07: Comparison of breast cancer molecular subtyping by Immunohistochemistry and by BluePrint® next generation RNA sequencing-based test at University Hospitals Leuven and Curie Institute Paris

Abstract Background MammaPrint® (MP) and BluePrint® (BP) are microarray-based tests with MP being prognostic for distant recurrence and BP enabling stratification into breast cancer molecular subtypes (Luminal, HER2, Basal-type). Recently, a CE marked MP and BP targeted RNA Next Generation Sequencing (NGS)-based kit was developed at Agendia and validated at University Hospitals Leuven and Curie Institute Paris. Here we compare breast cancer molecular subtype stratification defined by immunohistochemistry (IHC) and by MP and BP NGS- and microarray- based tests. Patients and Methods In this study, 124 primary operable invasive breast cancer patients were included at University Hospitals Leuven and at Curie Institute (n=80 Leuven; n=44 Curie) with the following histological subtypes: ductal-NOS (n=100), lobular (n=16), mucinous (n=3), tubular (n=2), others (n=3). Patients with bilateral breast cancer or with &amp;gt;3 positive lymph nodes were excluded. Surrogate breast cancer subtypes based on IHC were defined as follows: luminal if ≥10% estrogen receptor (ER) expression; triple negative if &amp;lt;10% ER and progesterone receptor (PR) expression and HER2 stained negative by IHC and/or FISH; HER2+ if HER2 receptor stained positive (2+ or 3+) by IHC and/or FISH. Luminal subtypes were further stratified into Luminal A-like (HER2 negative, Ki-67&amp;lt;14%, PR≥20%) and Luminal B-like (HER2 negative or positive, Ki-67 ≥14%, PR&amp;lt;20%). When Ki-67% was not available, tumors with grade 1 or 2 were classified as Luminal A-like and with grade 3 as Luminal B-like. IHC subtypes were compared to the BP NGS and microarray molecular subtypes (Luminal-, HER2- and Basal-type). To further stratify BP luminal type tumors, MP test was used as follows: Luminal A (BP Luminal and MP low risk) and Luminal B (BP Luminal and MP high risk). Results Concordance between IHC and MP/BP NGS subtyping was 75.0% (93/124), while concordance between MP/BP on NGS and microarray was 89.5% (111/124). MP/BP NGS subtyping identified more low risk Luminal A tumors compared to IHC (54.0%, (67/124) vs 44.3% (55/124)). Notably, concordance was excellent for triple-negative and, to less extent for HER2 driven tumors (Luminal B-like-HER2 positive and HER2+). IHC vs. MP/BP NGS molecular subtyping (n=124) MP/BP NGSIHCLuminal ALuminal BHER2-positiveBasalTotalLuminal A-like4690055Luminal B-like, HER2-negative16210037Luminal B-like, HER2-positive565016HER2-positive00303Triple negative0101213Total6737812124Microarray vs MP/BP NGS molecular subtyping (n=124) MP/BP NGSMicroarrayLuminal ALuminal BHER2 positiveBasalTotalLuminal A6040064Luminal B7310038HER2-positive028010Basal0001212Total6737812124 Conclusion This study shows a discordance of 25.0% between IHC and BP/MP NGS subtyping. This is in line with previous findings where IHC was compared to molecular subtyping based on microarray (Viale 2017, Whitworth 2014) underlining the complementarity of genomic testing in early stage breast cancer. Moreover, we observed a high concordance between NGS and microarray molecular subtyping, which suggests a successful translation of the MP/BP microarray test to a MP/BP NGS test. Citation Format: Darrigues L, Slembrouck L, Mittempergher L, Delahaye LJ, Vanden Bempt I, Vander Borght S, Vliegen L, Sintubin P, Raynal V, Bohec M, Reyes C, Rapinat A, Helsmoortel C, Jongen L, Hoste G, Neven P, Wildiers H, Smeets A, Nevelsteen I, Punie K, Van Nieuwenhuysen E, Han S, Laurent C, Vincent-Salomon A, Laas-Faron E, Witteveen AT, Neijenhuis S, Glas AM, Floris G, Reyal F. Comparison of breast cancer molecular subtyping by Immunohistochemistry and by BluePrint® next generation RNA sequencing-based test at University Hospitals Leuven and Curie Institute Paris [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-02-07.

Abstract P5-22-20: Oncologic safety of endoscopic assisted breast surgery compared with conventional breast surgery: An analysis of 1295 primary operable breast cancer patients from single institute

Abstract Background:Endoscopy-assisted breast surgery (EABS) performed through minimal axillary and/or periareolar incisions is a possible alternative to open surgery for certain patients with breast cancer. In this study, we report the oncologic safety results of EABS compared with conventional breast surgery (CBS). Methods: The medical records of patients who underwent EABS for breast cancer during the period June 2010 to April 2017 were collected from the EABS database at Changhua Christian Hospital, a tertiary medical center in central Taiwan. Data on clinicopathologic characteristics, type of surgery, method of breast reconstruction, margin involvement, locoregional recurrence, distant metastasis and overall survival were collected and compared to another cohort of patients, who received CBS at the same hospital, to determine the effectiveness and oncologic safety of EABS. Results: A total of 1295 patients were enrolled in current study, including 214 patients receiving EABS and 1081 patients underwent CBS. The mean age of them were 50.4 ± 9.4 years-old in EABS group, and 52.5 ± 11.3 in CBS group (P=0.01). Patients who received EABS were associated with more early stage breast cancer than patients with CBS group (P&amp;lt;0.01). The margin involved rate was 3.3% in EABS group, and 6.1% in CBS group (P=0.11). During a median follow-up of 57.7 ± 24.7 months, the locoregional recurrence was 3.7% in EABS group, and 7.3% in CBS group (P=0.06). The distant metastasis rate was 2.8% in EABS group and 10.3% in CBS group (P=0.001). The overall survival rate was 99.5% in EABS group, and 93.8% in CBS group. Comparison of endoscopic assisted breast surgery (EABS) and conventaional breast surgery (CBS) EABSCBSP value N=214 (%)N=1081 (%) Pathology tumor size (cm)2.2 ± 1.62.3 ± 1.70.414Operation method Mastectomy141 (65.9)530 (49.0)&amp;lt;0.001Breast conserving surgery73 (34.1)551 (51.0) Lymph node surgery SLNB only149 (69.6)534 (49.4)&amp;lt;0.001SLNB then ALND40 (18.7)244 (22.6) ALND7 (3.3)259 (24.0) Not done18 (8.4)44 (4.1) Breast reconstruction Yes108 (50.5)930 (86.0)&amp;lt;0.001No106 (49.5)151 (14.0) Lymph node metastasis Yes49 (24.7)375 (35.0).0.005No149 (75.3)797 (65.0) Stage 055 (25.7)160 (14.8)&amp;lt;0.001I67 (31.3)340 (31.5) II84(39.2)439(40.7) III8(3.8)136(12.6) Grade I35 (17.6)178 (17.2)0.365II118 (59.3)566 (54.8) III46 (23.1)288 (27.9) Margin status Involved7 (3.3)66 (6.1)0.110Not-involved207 (96.7)1015 (93.9) Locoregional recurrence Yes8 (3.7)79 (7.3)0.057No206 (96.3)1002 (92.7) Distance metastasis Yes6 (2.8)111 (10.3)0.001No208 (97.2)970 (89.7) Survival Yes213 (99.5)1014 (93.8)0.001No1 (0.5)67 (6.2) SLNB: sentinel lymph node biopsy, ALND: axillary lymph node dissection. Conclusion: The preliminary oncologic safety analysis from our institution showed that EABS is a safe procedure and results in low margin involved rate, and no increase of locoregional recurrence, distant metastasis or mortality compared with conventional breast surgery. However, this study might be biased due to its retrospective nature and possible selection bias.Ongoing case controlled comparison study will be performed to further consolidate the oncologic safety of endoscopic assisted breast surgery. Citation Format: Lai H-W, Chen S-T, Chen D-R, Kuo S-J. Oncologic safety of endoscopic assisted breast surgery compared with conventional breast surgery: An analysis of 1295 primary operable breast cancer patients from single institute [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-20.

The prognostic value of the tumour-stroma ratio in primary operable invasive cancer of the breast: a validation study.

The primary aim of the current study is to validate the prognostic relevance of the relative amount of tumour-associated stroma, the tumour-stroma ratio, in a large cohort of primary operable breast cancer patients. A retrospective cohort study was performed on women diagnosed and treated for primarily operable invasive breast cancer in the period from 1 January 1990 till 31 December 1999. Tumour-stroma ratio was estimated by microscopic evaluation of haematoxylin and eosin tumour slides. Two independent observers (k=0.68) performed tumour-stroma ratio evaluation in a significant part of the cohort. The prognostic potential with respect to overall, recurrence-free and distant metastasis-free survival was evaluated. A total of n=737 women were evaluated. Median follow-up time was 11.5years. High stromal content was an independent prognosticator for worse overall (hazard ratio 1.56, p=0.002, 95% confidence interval 1.18-2.05), distant metastasis-free (hazard ratio 1.52, p=0.008, 95% confidence interval 1.12-2.06) and recurrence-free survival (hazard ratio 1.35, p=0.046, 95% confidence interval 1.01-1.81). In subgroups of hormone receptor-positive and lymph node-negative cases, high stromal content was also an independent prognosticator for worse outcome. Tumour-stroma ratio is an independent risk factor for worse overall, distant metastasis-free and recurrence-free survival in primarily operable breast cancer. However, detailed prospective studies with respect to tumour-stroma ratio are necessary to gain more insight in its prognostic potential in clinical practice.

Abstract P4-02-03: The diagnostic accuracy of breast MRI in the prediction of malignant invasion of nipple areolar complex (NAC) of breast

Abstract Purpose: Nipple sparing mastectomy is increasingly used as a surgical treatment for breast cancer. To correctly predict the possibility of nipple invasion pre-operatively is critical important to prevent occult nipple invasion or early nipple recurrence. The objective of our study is to assess the diagnostic accuracy of breast MRI for the evaluation of malignant invasion of the nipple-areolar complex (NAC). Material and Methods: From January 2011 to December 2013, patients with primary operable breast cancer diagnosed and treated at Changhua Christian Hospital (CCH), Taiwan were searched. The inclusion criteria were primary operable breast cancer patients, who received pre-operative breast MRI, and received breast cancer operation at CCH. The exclusion criteria were patients whose primary tumor was removed before definite cancer operation, those who received neoadjuvant chemotherapy, or patient's detailed data not available. Breast MRI examinations were retrospectively reviewed for nipple invasion or retraction, periareolar skin thickening, nipple areolar complex enhancement, relationship to the subareolar mass, malignant mass pattern, thickness of nipple-areolar complex enhancement, tumor-nipple distance and tumor size, and were correlated with pathologic findings. The accuracy of breast MRI to predict nipple invasion was compared with pre-operative image and post-operative pathologic reports. Results: A total 704 primary operable breast cancers with pre-operative MRI and post operative pathologic reports were enrolled in our current study. In the total 704 patients, MRI showed signs of suspect NAC invasion in 160 (22.7%) patients. Total 41 (25.6%) patients were pathologic proven malignant invasion of NAC. In the final pathologic analysis, 57 pathologic confirmed NAC invasions were found in the 704 patients. The overall nipple invasion rate was 8.1% in this current study. The sensitivity of Breast MRI to predict NAC involvement was 71.9%. The Specificity of breast MRI to NAC invasion is 81.6%. The positive predictive value of breast MRI is 25.6%. The negative predictive value of breast MRI is 97.1%. The accuracy of breast MRI to predict NAC involvement is 80.8%. In univariate logistic regression analysis, tumor size, lymph node metastasis, central location of tumor, unilateral nipple enhancement, relationship to tumor, and HER-2 overexpression were prognostic factors for NAC invasion. In multivariate analysis, unilateral nipple enhancement (hazard ratio=4.944, CI: 1.938-12.616, P=0.001) was the most significant independently risk factor associated with the increased risk of NAC involvement. Multivariate analysis of factors related to nipple invasion Multivariate analysisParametersOdds ratio95% CIpMRI tumor size0.8500.716-1.0090.063Distance to nipples (cm)1.1990.931-1.5440.160Location of tumor (Central)1.6830.724-3.9120.226Nipple enhancement (Unilateral)4.9441.938-12.6160.001Relationship (Yes)1.6160.625-4.1770.322MRI Lymph node metastasis (Yes)1.6740.870-3.2240.123 Conclusion: MRI is an useful diagnostic image method for the evaluation of malignant invasion of the nipple-areolar complex. Through preoperative breast MRI evaluation of NAC status, more personalized oncoplastic breast surgery could be performed. Citation Format: Lai H-W, Chen S-T, Chen D-R, Wu H-K, Kuo S-J. The diagnostic accuracy of breast MRI in the prediction of malignant invasion of nipple areolar complex (NAC) of breast. [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 P4-02-03.

Abstract P6-09-11: Independent prognostic value of age depends on breast cancer subtype

Abstract Background: Young women present more often with aggressive breast cancer phenotypes and have worse prognosis. It remains controversial whether age is an independent prognostic factor in early stage breast cancer. Arbitrarily chosen age cut-off values have been proposed in different studies. Furthermore, few studies have examined the impact of breast cancer subtypes on the prognostic value of age. This abstract represents an update of a prior analysis (San Antonio Breast Cancer Symposium, December 4-8 2012, P06-07-29). Methods: We included all primary operable female breast cancer patients from our prospectively managed database in UZ Leuven, Belgium. We assessed the effect of age on locoregional free interval (LRRFI), distant metastasis interval (DMFI) and breast cancer specific survival (BCSS). In univariate analysis, using Cox regression models, we determined the best categorization of age at diagnosis into two or three age groups by considering all possible combinations of cut-off values. Best categorization was obtained with three age groups. We further determined, using multivariate analysis (correcting for phenotype, tumor size, nodal status, adjuvant chemo -, hormone – and radiotherapy, type of surgery and procedure of axillary staging), whether age at diagnosis remains an independent predictor of outcome (LRRFI, DMFI and BCSS). We further explored whether age at diagnosis is an independent predictor of event risk (LRRFI, DMFI and BCSS) in different breast cancer subtypes. Luminal A-like (grade I or II, ER and/or PR positive, HER 2 positive), Luminal B-like (idem but grade III), Luminal HER 2 like (ER and/or PR positive, HER 2 positive), HER 2 like (ER/PR negative, HER 2 positive), triple negative (ER/PR negative, HER 2 negative). Results: We included 4180 patients with a mean/median age of 58/57 year and with a median follow up of 8.9 year. Multivariate analysis confirmed age as an independent prognostic variable for LRRFI, DMFI and BCSS. Results multivariable analysis with age in 3 groups (HR (95% CI) P-VALUE) LRRFIDMFIBCSSYoungest versus middle1.61 (1.18-2.18) 0.00251.54 (1.23-1.93) 0.00021.72 (1.26-2.36) 0.0007Youngest versus oldest3.45 (1.85-6.45) 0.00011.25 (0.89-1.77) 0.19821.31 (0.85-2.02) 0.2220Middle versus oldest2.15 (1.22-3.79) 0.00820.81 (0.61-1.09) 0,17060.76 (0.55-1.06) 0.1014 We found optimal cut-off values for LRRFI at 44y and 72y, for DMFI at 47y and 71y and for BCSS at 41y and 70y. In an exploratory analysis, with age as continuous variable, by subtype we found a significant independent association between age and LRRFI (P=0.0169), DMFI (P=0.0344) in luminal A-like, LRRFI (P=0.0022) in luminal B-like and DMFI (P=0.0010) and BCSS (P=0.0053) in triple negative breast cancer. No significant associations were found in luminal HER2 and HER2 like breast cancers. Conclusion: This study has shown that young age is an independent prognostic factor for LRRFI, DMFI and BCSS after correction for the most important clinical prognostic factors. The prognostic effect is most important in luminal A and triple negative subtypes. Additional analyses for subtypes with age as a categorical variable will be performed and optimal cut off values will be defined. Citation Format: Poppe A, Brouckaert O, Laenen A, Soubry A, Remmerie C, Floris G, Leunen K, Berteloot P, Amant F, Vergote I, Nevelsteen I, Smeets A, Christiaens M-R, Weltens C, Peeters S, Van Limbergen E, Wildiers H, Neven P. Independent prognostic value of age depends on breast cancer subtype. [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 P6-09-11.

Tertiary lymphoid structures are associated with higher tumor grade in primary operable breast cancer patients.

BackgroundTertiary lymphoid structures (TLS) are highly organized immune cell aggregates that develop at sites of inflammation or infection in non-lymphoid organs. Despite the described role of inflammation in tumor progression, it is still unclear whether the process of lymphoid neogenesis and biological function of ectopic lymphoid tissue in tumors are beneficial or detrimental to tumor growth. In this study we analysed if TLS are found in human breast carcinomas and its association with clinicopathological parameters.MethodsIn a patient group (n = 290) who underwent primary surgery between 2011 and 2012 we assessed the interrelationship between the presence of TLS in breast tumors and clinicopathological factors. Prognostic factors were entered into a binary logistic regression model for identifying independent predictors for intratumoral TLS formation.ResultsThere was a positive association between the grade of immune cell infiltration within the tumor and important prognostic parameters such as hormone receptor status, tumor grade and lymph node involvement. The majority of patients with high grade infiltration of immune cells had TLS positive tumors. In addition to the degree of immune cell infiltration, the presence of TLS was associated with organized immune cell aggregates, hormone receptor status and tumor grade. Tumors with histological grade 3 were the strongest predictor for the presence of TLS in a multivariate regression model. The model also predicted that the odds for having intratumoral TLS formation were ten times higher for patients with high grade of inflammation than low grade.ConclusionsHuman breast carcinomas frequently contain TLS and the presence of these structures is associated with aggressive forms of tumors. Locally generated immune response with potentially antitumor immunity may control tumorigenesis and metastasis. Thus, defining the role of TLS formation in breast carcinomas may lead to alternative therapeutic approaches targeting the immune system.

Stepwise Implementation of a Specialist Breast Nurse Position and Clinical Pathway: Impact on Patient Satisfaction

Background: Key success factors for significantly improving patient satisfaction on breast cancer care are not well known. Data obtained over a period of 6 years in a breast cancer clinic provide a portrait of the evolution of patient satisfaction on quality of care. Methods: We measured 19 patient satisfaction items and 6 groups of 60 consecutive Primary Operable Breast Cancer patients filled in the (validated) questionnaire. A first group prior and a second group after the implementation of a clinical pathway, a third group after the introduction of a breast cancer nurse following patients systematically only postoperatively, a fourth group having an additional consultation of the breast nurse in the diagnostic and preoperative phase and a fifth and sixth group after implementing education sessions for hospital staff and the Eusoma and other national guidelines. Results: We found that the successive modifications of the care process resulted in an improvement of patient satisfaction for all items and for 16 of the 19 items these improvements were significant. The number of items for which dissatisfaction was higher than 5% diminished from 18 to 3 of the 19 items (group 6 versus group 1). Conclusion: Significant improvements were only achieved by combining the implementation of a clinical pathway, a specialist breast nurse, education sessions and Eusoma and national guidelines. In particular, the role of the specialist breast cancer nurse was found to be of major importance to coordinate the care process and guide patients through the pre- and post-operative phase of their treatment.

Abstract P6-07-29: Independent prognostic value of age depends on breast cancer subtype

Abstract Background: Whether age is an independent prognostic factor in early breast cancer remains controversial. Different cut-off values have been suggested in different studies and few studies assessed its value in triple negative breast cancer and other phenotypes. Methods: We included all primary operable breast cancer patients from our prospectively managed database in UZ Leuven, Belgium. We excluded male patients, patients treated elsewhere first, patients treated with primary systemic treatment first. We assessed the effect of age as a continuous and categorical variable for distant metastasis free interval (DMFI), locoregional free interval (LRRFI) and breast cancer specific survival (BCSS) in multivariable analysis (correcting for phenotype, tumor size, nodal status, chemo−, endocrine−, radiotherapy, type of breast and axillary surgery). We assessed the effect of age for DMFI, LRRFI and BCSS in basal-like breast cancer and other phenotypes. Results: We included 4318 patients with a mean/median age of 58/ 57 years (1170 patients were younger than 50 years) and with a median follow-up of 6,0 years. Multivariate analysis confirmed age as an independent prognostic variable for LLRFI (HR1.91; 95% CL:1.33–2.74; p = 0.0005), DMFI (HR:1.77; 95% CL:1.33–2.36; P &amp;lt; 0.0001) and BCSS (HR:2.35; 95% CL:1.66–2.74; P &amp;lt; 0.0001). The optimal cut-off value is 41years for LLRFI and BCSS and 44 years for DMFI. We did not find an independent prognostic value for age in triple negative breast cancer regarding DMFI and LRRFI. Results for other subtypes are subject to currently ongoing analyses. Conclusions: Overall, young age in primary operable breast cancer patients is an independent prognostic value for DMFI, LRRFI and BCSS after adjusting for known prognostic factors. In triple negative breast cancer, age did not retain independent prognostic value for DMFI and LRRFI. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-29.

Abstract P6-07-19: Prognostic relevance of PR and detection mode in Luminal Her-2 negative breast cancer

Abstract Introduction: Although known to hold prognostic value, PR status is not used to discriminate luminal A from luminal B HER2 negative breast cancers. We will here assess whether PR (and also detection mode) is an independent prognostic variable in luminal HER2 negative breast cancer and whether the prognostic value of PR is grade dependent. Patients and methods: Primary operable breast cancer patients diagnosed between 1/1/2000 and 31/12/2009 treated in UZ Leuven were retrieved from the prospectively managed database (n = 4318). Her-2 status was missing in 93 and ER/PR in 2 patients. Of the remaining patients, 3330 were luminal (ER and/or PR positive) HER2 negative (full cohort details: Brouckaert O., et al. Ann Oncol. 2012 Apr 6). Missing values were observed in 137 patients (4.1%), and these were imputed using ‘multivariate imputation by chained equations’. A competing risks proportional hazards model was used for multivariable analysis (includes age, size, grade, screening, palpability, nodal status, histology, type of surgery, radiotherapy, endocrine and chemotherapy) of distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS). We used a predefined set of predictors, investigated non-linearity of the predictor effects, checked the proportional hazards assumption, and tested for interactions with grade. Results: Median follow-up was 76 months and 5-year survival probability 93%. PR is an independent prognostic variable but this is grade dependent for DMFI, but not for BCSS (interaction p = 0.15), although PR positivity was mainly protective for grade 3 breast cancers again (table 1). Palpability is a strong prognostic variable for DMFI and BCSS and was strongly correlated with screen detection (yes/no) and here, we found no evidence of grade dependency. Conclusion: PR status and palpability may further refine prognosis of patients with luminal HER2 negative breast cancers. For PR, prognostic value is grade dependent, but for palpability, this is grade independent. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-19.

High serum HER2 extracellular domain levels: correlation with a worse disease-free survival and overall survival in primary operable breast cancer patients

High serum human epidermal growth factors receptor-2 (HER2) extracellular domain (ECD) has been identified as an independent prognostic indicator of poor prognosis in metastatic breast cancer. However, its prognostic value in primary operable breast cancer was still controversial. We aim to investigate the correlation between serum HER2 ECD levels and tissue HER2 status, the association between serum HER2 ECD levels and clinicopathological characteristics, and their impacts on disease-free survival (DFS) and overall survival (OS) in primary operable breast cancer. Two hundred and fifty-two primary operable breast cancer patients pretreated from 2002 to 2009 in Sun Yat-Sen University Cancer Center were enrolled in this study. Serum HER2 ECD was measured by chemiluminescent assay, and tissue HER2 status was accessed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) assay. There was a significant correlation between serum HER2 ECD levels and HER2 tissue status (P < 0.001, R = 0.36). High serum HER2 ECD levels (≥15 ng/mL) were significantly associated with age (≥35 years) (P = 0.028), postmenopausal status (P < 0.001), stage III (P < 0.001), tumor size (≥2 cm) (P < 0.001), lymph node involvement (P < 0.001), negative estrogen receptor (P = 0.005), and progesterone receptor status (P = 0.001). Multivariate analysis showed that high serum HER2 ECD level was an independent prognostic factor of worse DFS (P = 0.014) and OS (P = 0.014) in primary operable breast cancer patients. Serum HER2 ECD level can reflect tissue HER2 status and can be an independent prognostic indicator for primary operable breast cancer patients.

Enhancer of Zeste Homologue 2 Expression in Breast Carcinoma Smears in Relationship with p53, Ki-67 and Other Prognostic Parameters

Background: The polycomb group protein enhancer of zeste homologue 2 (EZH 2) has been reported as a marker of aggressive breast cancer. The aim of this study was to investigate the correlation between the expression of EZH 2 with p53 and Ki-67 expression and other clinicopathological parameters in primary breast carcinomas in order to determine the role of the above marker as a prognosticator of tumor aggressiveness and patient outcome. Patients and Methods: One hundred primary operable breast cancer patients were investigated in order to identify the expression of EZH 2, Ki-67 and p53 in imprint smears immunocytochemically. The prevalence of expression of these markers was then correlated with clinicopathological parameters. Follow-up was available for all patients. Results: EZH 2 was expressed in 64% of the cases and correlated with higher levels of p53 (relative risk = 3.00, p < 0.0001) and Ki-67 (relative risk = 3.25, p < 0.0001). Malignant cells showed immunoreactivity for all markers in the nucleus. Univariate analysis revealed a strong association between EZH 2 protein expression and tumor grade and size, lymph node metastasis, and HER-2 and estrogen and progesterone receptor status. Multivariable statistical analysis revealed that lymph node metastasis was the main predictor for EZH 2 expression. Decreased patient survival was also significantly associated with EZH 2 expression (p < 0.0001). Conclusions: EZH 2 expression may be a marker of poor prognosis in breast carcinoma patients and has been suggested as a candidate for targeted therapy.

Abstract P2-02-09: The Effect of Breast-MRI in Work-Up of Primary Operable Breast Cancer

Abstract Background: Breast magnetic resonance imaging (MRI) is becoming an often-utilized examination in the preoperative planning for breast cancer. However, it is not yet accepted as a routine examination for all breast cancer patients due to the lack of data regarding whether breast MRI has any effect on recurrence or survival. Aim: The aim of this study is to evaluate the effect of MRI on surgical management in operable breast cancer. Methods: From April 2008 till January 2010 consecutive primary operable breast cancer patients had a preoperative breast-MRI in addition to regular mammography and ultrasonography. Additional lesions newly found by MRI were evaluated with a target ultrasound and if needed biopsied. Moreover MRI tumor size was compared to mammographic and ultrasonographic tumor size. Blinded for MRI results and the performed surgical plan, surgical management based on traditional radiological work-up was determined retrospectively by 2 surgeons. Change of surgical plan by MRI was subsequently analysed. Accuracy of MRI based surgical plan was evaluated by comparing definitive pathology. Results Hundred ninety eight consecutive patients were analyzed. Median age was 59 years (23-82). Additional ipsilateral and contralateral suspicious lesions were detected by MRI in 53 patients (27%). Twenty two patients had additionally target-ultrasonography: 5 lesions were not found, 4 lesions had benign aspect. Five out of 13 biopsied patients had second breast cancer, 3 patients had contralateral breast cancer and 2 patients had multicentric breast cancer. In 31 patients no further evaluation was performed because the new focus was supposed to be a satellite (n=12) or mastectomy was already chosen to be done (n=19). There was a change in surgical plan due to MRI results in 35 of 198 patients (18%), all of whom received more extensive surgery than previously planned: in 17 patients mastectomy was performed instead of lumpectomy, 15 patients had a more extensive lumpectomy. Three patients had contralateral surgery for breast cancer. In 24 patients (69%) MRI based surgical plan was confirmed by definitive pathology. In 11 patients MRI overestimated tumor size or misinterpreted a satellite lesion. Conclusion. Breast MRI contributes to a significantly change of surgical plan. However, false-positive findings are frequent. Therefore, in unselected primary operable breast cancer patients routine implementation of breast MRI is not right away justified. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-09.

Improving NPI for breast cancer prognosis by including PR and HER-2 expression: own data and external validation set.

Abstract Abstract #1080 The Nottingham Prognostic Index (NPI) classifies primary operable breast cancer patients into good (NPI ≤ 3.4) , intermediate (NPI 3.4-5.4) and poor (NPI ≥ 5.4) prognostic risk groups [Br J Cancer 1987; 56: 489–92]. Studies indicate a significant short term prognostic role for estrogen (ER), progesterone (PR) and HER-2 receptor on disease free survival (DFS). We proposed at SABCS 2007 to add PR and HER-2 expression to the NPI called improved NPI (iNPI) defined as (NPI) + (HER-2) – (PR), with HER-2 and PR '1' in case of amplified HER-2 and any PR-expression and '0' otherwise.&amp;#x2028; Internal validation of the iNPI was performed on 1928 breast cancer patients, primary operated between Jan 2000 and June 2005 at Univ Hospital Leuven. All patients were classified into any of the three NPI or iNPI risk group. Mean follow-up was 3.5 yrs and DFS was defined as previously stated [Breast Cancer Research and Treatment 2007; 106: S247-S247]. Out of the 601 patients classified as NPI low risk, 59 shifted towards the intermediate iNPI group. Comparison of DFS for the 59 shifted with the non-shifted patients from the low NPI class did not reveal a significant difference (p=0.129, log-rank test). 57 patients out of 935 and 136 out of 392 respectively classified as intermediate and high NPI group became high and intermediate risk according to the iNPI. In both cases, DFS of the shifted patients differed significantly from DFS of the non-shifted patients (p=&amp;lt;.001 en p=0.029). DFS of the shifted patients with the iNPI group they where shifted to was not/marginally significant (p=0.856, p=0.462 and p=0.047 for low, intermediate and high NPI respectively).&amp;#x2028; For external validation a dataset from the Breast Cancer Micrometastasis group in Oslo with 677 patients and known NPI, PR and HER-2 was used. Figure 1 confirms a significant difference between DFS of the shifted and the non-shifted patients within the highest NPI risk group (p=0.021). The difference in DFS between shifted and non-shifted patients was marginally non-significant (p=0.068) in the intermediate and non-significant in the low NPI group (p=0.116). The non-significant difference between DFS of the shifted groups with the DFS of the group they were shifted to was confirmed, with exception of the low NPI group (difference in systemic treatment) (p=0.040, p=0.621 and p=0.076 for low, intermediate and high NPI respectively).&amp;#x2028; We confirm the results from an internal study at the Univ Hospital in Leuven on an external dataset. Inclusion of the PR and HER-2 status into the NPI results in more homogenate risk groups concerning DFS.&amp;#x2028; &amp;#x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1080.

Short course dose-dense (dd) epirubicin (E) and cyclophosphamide (C) as neo-adjuvant chemotherapy for stage II-IIIA breast cancer (BC)

11543 Background: Neo-adjuvant anthracycline (A)- and taxane (T)-based chemotherapy has become a standard option for primary operable BC patients (pts) who are candidates for adjuvant chemotherapy, irrespective of the size of the tumor. However, the addition of T is not an established adjuvant treatment in N0 tumors. Aim of this study was to evaluate response and tolerability of a short course of neo- adjuvant dd-EC-based chemotherapy in clinical stage II-IIIA BC. Methods: In a prospective phase II study, women with histologically confirmed diagnosis of BC, aged 18–75 years, clinical stage T2-T3 and N0–1, were treated with 4 cycles of intravenous E 90 mg/m2 d1/q14 and C 600 mg/m2 d1/q14. PEG-filgrastim (PEG-F) was given on day 2 of each cycle. Following surgery, responding pts with pathological N0 tumors received 3 to 4 cycles of adjuvant EC q21. Unresponsive or pN1 pts received paclitaxel 80 mg/m2 weekly for 12 weeks. Overall response rate and toxicity were the primary endpoints of the study. Results: Si...

The Shaping of a Polyvalent and Highly Individual T-Cell Repertoire in the Bone Marrow of Breast Cancer Patients

We analyzed the T-cell repertoires from the bone marrow of 39 primary operated breast cancer patients and 11 healthy female donors for the presence and frequencies of spontaneously induced effector/memory T lymphocytes with peptide-HLA-A2-restricted reactivity against 10 breast tumor-associated antigens (TAA) and 3 normal breast tissue-associated antigens by short-term IFN-gamma enzyme-linked immunospot (ELISpot) analysis. Sixty-seven percent of the patients recognized TAAs with a mean frequency of 144 TAA reactive cells per 10(6) T cells. These patients recognized simultaneously an average of 47% of the tested TAAs. The T-cell repertoire was highly polyvalent and exhibited pronounced interindividual differences in the pattern of TAAs recognized by each patient. Strong differences of reactivity were noticed between TAAs, ranging from 100% recognition of prostate-specific antigen(p141-149) to only 25% recognition of MUC1(p12-20) or Her-2/neu(p369-377). In comparison with TAAs, reactivity to normal breast tissue-associated antigens was lower with respect to the proportions of responding patients (30%) and recognized antigens (27%), with a mean frequency of only 85/10(6) T cells. Healthy individuals also contained TAA-reactive T cells but this repertoire was more restricted and the frequencies were in the same range as T cells reacting to normal breast tissue-associated antigens. Our data show a highly individual T-cell repertoire for recognition of TAAs in breast cancer patients. This has potential relevance for T-cell immune diagnostics, for tumor vaccine design, and for predicting immune responsiveness.