The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases

BACKGROUND:

Brain metastases (BM) arising from triple‐negative breast cancer (TNBC) portend a poor prognosis. TNBC is more common in premenopausal and African‐American (AA) patients; both of these characteristics also confer a poor prognosis. In a single‐institution cohort study, the authors attempted to determine whether the inferior outcome noted with TNBC brain metastases is more reflective of a higher risk population or the subtype itself.

METHODS:

The University of North Carolina Breast Cancer Database identified patients with BC brain metastases who were diagnosed between 1988 and 2008. BC subtype was assigned by immunohistochemistry: hormone receptor (HR) positive (+);(HR, estrogen receptor [ER]+ and/or progesterone receptor [PR]+)/human epidermal growth factor receptor 2 (HER2) negative (‐), HR+/HER2+, HR‐/HER2+, and TN (ER‐/PR‐/HER2‐). Survival and disease recurrence patterns were evaluated by subtype, patient age (<40 years vs ≥40 years), and race (AA vs non‐AA) using the Kaplan‐Meier method and Cox regression analysis.

RESULTS:

Among 119 patients with BC brain metastases, 33% were AA and 31% were aged <40 years. BC subtype was confirmed in 98 patients (30% with HR+/HER2‐, 21% with HR+/HER2+, 18% with HR‐/HER2+, and 31% with TNBC). Survival after BM was found to be impacted by subtype (P = .002), and was shortest for patients with TNBC (0.24 years; 95% confidence interval, 0.17 years‐0.48 years). There were no age‐specific (P = .84) or race‐specific (P = .09) differences in survival noted after brain metastases; stratification of BC subtypes by age and race revealed no difference (all, P > .1). The receipt of systemic therapy after BC brain metastases was found to be an important predictor of survival after BC brain metastases (hazard ratio, 0.29; P = .002) when adjusted for race, age, number of central nervous system lesions, and BC subtype.

CONCLUSIONS:

TNBC confers a high risk of death after brain metastases regardless of patient race and age, supporting the need for novel agents capable of controlling both intracranial and extracranial TNBC across all races and ages. Cancer 2011. © 2010 American Cancer Society.     

不同病理亚型乳腺癌脑转移患者预后分析

目的:了解不同病理亚型乳腺癌脑转移患者的预后特点。方法:根据肿瘤组织免疫组化ER、PR、HER-2 的表达情况将89例患者分为4 组:Luminal A型（ER+ 和/或PR+ ,HER-2-）17例、Luminal B型（ER+ 和/或PR+ ,HER-2 +）15例、HER-2 + 型（ER- ,PR- ,HER-2 +）24例和Basal-like型（ER- ,PR- ,HER-2-）33例。主要观察4 组患者分布比例、发病年龄、月经状态、病理类型、病理分级、肿瘤大小、淋巴结状态及脑转移发生距手术时间及部位等。使用SPSS15.0 统计软件进行数据分析,定量资料采用t检验,计数资料比较采用卡方检验,生存率计算采用Kaplan-Meier 法并用Log-rank 检验,P<0.05为差异有统计学意义。结果:所有患者当中Basal-like型所占比例最高（37.1%）,其次为HER-2 +（27%）,Luminal A型（19.1%）,Luminal B型最少（16.9%）。 Basal-like 型患者预后最差,其病理分级Ⅲ级的患者比例达到了73% 。在其他部位出现转移情况上,Luminal型患者表现出较高的骨转移倾向。全组患者的中位生存期为47个月,无病生存期为20个月,确诊脑转移后的生存期为9 个月。ER（-）且PR（-）较ER/PR（+）（45个月vs.52个月,P=0.006）、HER-2（+）较HER-2（-）（45个月vs.51.5 个月,P=0.04）、Basal-like亚型的患者预后较其他亚型差（33个月vs.52个月,P=0.000）。 结论:病理亚型是判断乳腺癌脑转移患者预后不同的良好指标,ER（-）且PR（-）、HER-2（+）、Basal-like亚型患者容易出现脑转移且预后较差。      

可手术的不同分子亚型乳腺癌的临床特征和生存分析

目的 分析Luminal A型、Luminal B型、人表皮生长因子受体2(HER-2)型和Basal-like型4种乳腺癌亚型的临床特征和生存状况,探讨乳腺癌个体化综合治疗的理论基础.方法 回顾性分析经手术治疗、资料完整、免疫组化方法能明确判定受体状况的乳腺癌患者408例,比较各型乳腺癌的临床特征、复发转移及生存情况.结果 Luminal A型248例,占60.8%;Luminal B型32例,占7.8%;HER-2型51例,占12.5%;Basal-like型77例,占18.9%.HER-2型乳腺癌≤45岁者明显少于其他亚型,Basal-like型乳腺痛发生腋窝淋巴结转移者的比例低于其他亚型,Luminal B型晚期病例多于其他亚型,而HER-2型早期病例多于其他亚型.获得随访的243例患者中,复发或转移58例,死亡51例.Luminal A型的复发转移率明显低于Luminal B型和Basal-like型(均P<0.05).Luminal A型、Luminal B型、HER-2型和Basal-like型的5年生存率分别为89.83%、86.15%、86.70%和79.85%,Luminal A型高于Basal-like型(P=0.008).Luminal A型、Luminal B型、HER-2型和Basal-like型的5年无病生存率分别为83.52%、68.88%、75.83%和71.66%,Luminal A型高于Luminal B型和Basal-like型(P=0.0481和P=0.0306).结论 中国人各亚型乳腺癌的构成比与欧美国家接近,Luminal A型是最常见的乳腺癌亚型,预后较好,Basal-like型和Luminal B型所占比例较小,但预后较差.     

Molecular Subtypes of Indonesian Breast Carcinomas - Lack of Association with Patient Age and Tumor Size

Objective: Breast carcinoma (BC) is a heterogeneous disease that exhibits variation in biological behaviour, prognosis and response to therapy. Molecular classification is generally into Luminal A, Luminal B, HER2+ and triple negative/basal-like, depending on receptor characteristics. Clinical factors that determined the BC prognosis are age and tumor size. Since information on molecular subtypes of Indonesian BCs is limited, the present study was conducted, with attention to subtypes in relation to age and tumor size. Methods: A retrospective cross-sectional study of 247 paraffin-embedded samples of invasive BC from Dr. Sardjito General Hospital Yogyakarta in the year 2012- 2015 was performed. Immunohistochemical staining using anti- ER, PR, HER2, Ki-67 and CK 5/6 antibodies was applied to classify molecular subtypes. Associations with age and tumor size were analyzed using the Chi Square Test. Results: The Luminal A was the most common subtype of Indonesian BC (41.3%), followed by triple negative (25.5%), HER2 (19.4%) and luminal B (13.8%). Among the triple negative lesions, the basal-like subtype was more frequent than the non basal-like (58.8 % vs 41.2%). Luminal B accounted for the highest percentage of younger age cases (< 40 years old) while HER2+ was most common in older age (> 50 years old) patients. Triple negative/basal-like were commonly large in size. Age (p = 0.080) and tumor size (p = 0.462) were not significantly associated with molecular subtypes of BC. Conclusion: The most common molecular subtype of Indonesian BC is luminal A, followed by triple-negative, HER2+ and luminal B. The majority of triple-negative lesions are basal-like. There are no association between age and tumor size with molecular subtypes of Indonesian BCs.     

双侧原发性乳腺癌ER、PR及HER-2表达特征及其与预后的关系

目的探讨雌激素受体（ER）、孕激素受体（PR）及人表皮生长因子受体2（HER-2）表达状态在双侧原发性乳腺癌（bilateral primary breast cancer,BPBC）患者第一癌与第二癌间的异同及其与预后的关系。方法回顾1961年1月至2007年12月间本院收治并确诊的565例BPBC患者临床资料,BPBC患者占同期全部乳腺癌患者的2．09％,其中同时性双侧乳腺癌（以6个月为界）198例占35．04％。采用免疫组织化学SP法进行ER、PR、HER-2检测。采用SPSS14．0中X^2检验比较ER、PR、HER-2在同时性和异时性BPBC表达的一致率及BPBC第一癌与第二癌ER、PR、HER-2的阳性率;采用Kaplan—Meier生存分析法研究BPBCER、PR和HER-2与患者预后的关系。结果同时性双侧原发性乳腺癌激素受体表达一致率要高于异时性双侧原发性乳腺癌（ER：X^2=5．30,P=0．02;PR：X^2=15．88,P=0,00）。双侧原发性乳腺癌两侧癌灶ER、PR和HER-2的表达没有区别（ER：X^2=2．02,P=0．16;PR：X^2=0．86,P=0．35：HER-2：X^2=0．70,P=0．79）。BPBC两侧ER和HER-2表达状况与其预后相关（ER：P=0．03,HER-2 P=0．03）。结论BPBC两侧癌灶激素受体及HER-2表达状态相仿。同时性BPBCER、PR表达的一致性高于异时性BPBC。两侧乳腺癌均检测激素受体和HER-2的表达对预后判断有一定的指导意义。     

Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation

We assessed differences in locoregional outcome based on receptor status combinations in a cohort of stage II–III breast cancer patients treated with modern trimodality therapy. Medical records of 582 consecutively treated patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 were reviewed. Rate of local regional recurrence (LRR) was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Gray’s test and by Fine and Gray’s modeling approach. Median follow-up was 44.7 months. Five-year progression-free survival (PFS) was 73.9% and overall survival (OS) was 84%. The cumulative 5-year incidence of LRR as first site of failure was 6.2% (95% CI 4.2–8.7). Five-year cumulative incidence of LRR was 8.6 versus 4.4% for estrogen receptor (ER) negative versus ER positive (P = 0.017), 8.5 versus 3.4% for progesterone receptor (PR) negative versus PR positive (P = 0.011), and 1.7 versus 7.5% for HER2 positive (86% received trastuzamab) versus HER2 negative (P = 0.032). Five-year cumulative incidence of LRR was 11.8% for the triple negative subtype and 3.9% for other receptor combinations (P < 0.001). Among patients whose disease is ER positive, 5-year LRR rate was 7.8 versus 3.4% for PR negative versus PR positive (P = 0.130). The prognostic value of the triple negative and HER2 negative subtypes was maintained on multivariate analysis. In the era of HER-2 targeted therapy, tumors that are HER-2 over expressing and are treated with trastuzumab have a very low rate of LRR. ER negative, PR negative, and triple negative status are associated with increased risk of LRR.     

Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program

BackgroundMale breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part I, a retrospective joint analysis of cases diagnosed during a 20-year period.MethodsPatients with follow-up and tumor samples, treated between 1990 and 2010, in 93 centers/9 countries. Samples were centrally analyzed in three laboratories (the United Kingdom, the Netherlands and the United States).ResultsOf 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001 and 2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo)adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% estrogen receptor (ER)-positive; 81.9% progesterone receptor (PR)-positive; 96.9% androgen receptor (AR)-positive [ER, PR or AR Allred score ≥3]; 61.1% Ki67 expression low (<14% positive cells); using immunohistochemistry (IHC) surrogates, 41.9% were Luminal-A-like, 48.6% Luminal-B-like/HER-2-negative, 8.7% HER-2-positive, 0.3% triple negative. Median follow-up: 8.2 years (0.0–23.8) for all, 7.2 years (0.0–23.2), for M0, 2.6 years (0.0–12.7) for M1 patients. A significant improvement over time was observed in age-corrected BC mortality. BC-specific-mortality was higher for men younger than 50 years. Better overall (OS) and recurrence-free survival (RFS) were observed for highly ER+ (P = 0.001), highly PR+ (P = 0.002), highly AR+ disease (P = 0.019). There was no association between OS/RFS and HER-2 status, Ki67, IHC subtypes nor grade.ConclusionsMale BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in >90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.     

Tumor Mutation Burden Prediction Model in Egyptian Breast Cancer patients based on Next Generation Sequencing

Objectives: This study aimed to identify the tumor mutation burden (TMB) value in Egyptian breast cancer (BC) patients. Moreover, to find the best TMB prediction model based on the expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER-2), and proliferation index Ki-67. Methods: The Ion AmpliSeq Comprehensive Cancer Panel was used to determine TMB value of 58 Egyptian BC tumor tissues. Different machine learning models were used to select the optimal classification model for prediction of TMB level according to patient’s receptor status. Results: The measured TMB value was between 0 and 8.12/Mb. Positive expression of ER and PR was significantly associated with TMB ≤ 1.25 [(OR =0.35, 95% CI: 0.04–2.98), (OR = 0.17, 95% CI= 0.02-0.44)] respectively. Ki-67 expression positive was significantly associated with TMB >1.25 than those who were Ki-67 expression negative (OR = 9.33, 95% CI= 2.07-42.18). However, no significant differences were observed between HER2 positive and HER2 negative groups. The optimized logistic regression model was TMB = -27.5 -1.82 ER – 0.73 PR + 0.826 HER2 + 2.08 Ki-67. Conclusion: Our findings revealed that TMB value can be predicted based on the expression level of ER, PR, HER-2, and Ki-67.     

Expression of HER2neu in ductal carcinoma in situ is associated with local recurrence

AimsDetermination of the risk of recurrence after local excision of ductal carcinoma in situ (DCIS) remains a challenge. Molecular profiling based on immunohistochemical staining to oestrogen receptor (ER), progesterone receptor (PR) and HER2neu improved risk prediction in invasive breast cancer, but few studies have evaluated if molecular classification of DCIS predicts local recurrence. We evaluated the expression of ER, PR and HER2neu in DCIS to determine if molecular classification predicts local recurrence after breast-conserving therapy for DCIS.Materials and methodsWe reviewed the records of patients with DCIS treated between 1987 and 2000, carried out a pathology review and immunohistochemical staining for ER, PR and HER2neu and categorised cases into four molecular phenotypes [luminal A (ER+ and/or PR+, HER2neu–), luminal B (ER+ and/or PR+, HER2neu+), HER2neu subtype (ER–, PR–, HER2neu+), triple negative (ER–, PR–, HER2neu–)]. We evaluated the association between the molecular subtype and the development of local recurrence.ResultsIn total, 180 cases of DCIS were included in the study (luminal A, n = 113; luminal B, n = 25; HER2neu type, n = 29; triple negative, n = 13). The median follow-up time was 8.7 years. We observed higher rates of local recurrence among luminal B (40%) and HER2neu type (38%) DCIS compared with luminal A (21%) and triple negative (15%) DCIS. On multivariable analysis, HER2neu overexpression was associated with an increased risk of local recurrence (hazard ratio = 1.98; 95% confidence interval: 1.11, 3.53, P = 0.02).ConclusionHER2neu expression in DCIS is a significant predictor of local recurrence, whereas luminal A and triple negative phenotypes are associated with relatively low risks of local recurrence.     

Patterns of Recurrence after Breast-Conserving Treatment for Early Stage Breast Cancer by Molecular Subtype

Purpose

To study clinical features and patterns of recurrence after breast-conserving treatment (BCT) for three molecular subtypes of early stage breast cancer.

Methods

The sample studied included 596 patients with T1-2N0-1 breast cancer who received BCT. Three groups were defined by receptor status. Luminal: estrogen receptor (ER) or progesterone receptor (PR) positive; triple negative (TN): ER, PR, and epidermal growth factor receptor-2 (HER2) receptor negative; and HER2 overexpressing: ER and PR negative but HER2 receptor positive.

Results

The number of patients in each group was 408 (68.5%), 105 (17.6%), and 83 (13.9%), respectively. The median follow-up period was 79 months. The TN and HER2 subtypes occurred in younger patients (p=0.0007) and had higher nuclear grade and poorer histologic grade (p<0.0001 and 0.0071, respectively). During the follow-up period, locoregional recurrence was detected as the first site of recurrence in 26 (6.4%), 11 (10.5%), and 9 (10.8%) patients in the luminal, TN, and HER2 subtypes, respectively (p=0.1924). Thirty-one (7.6%), 7 (6.7%), and 7 (8.4%) patients in each group had distant metastases as the first sign of recurrence (p=0.8996). Median time to locoregional and distant recurrence was shorter in the HER2 subtype (p=0.0889 and 0.0780, respectively), and the HER2 subtype was significantly associated with poor overall survival (p=0.0009).

Conclusion

After BCT in Korean women with early stage breast cancer, the patterns of recurrence were not different among the molecular subtypes, although the TN and HER2 subtypes were associated with younger age, higher nuclear grade, and poorer histologic grade.     

Hepatic resection for breast cancer liver metastases: Impact of intrinsic subtypes

IntroductionThe role of surgery for breast cancer liver metastases (BCLM) remains controversial. This study aimed to analyze survival in patients treated with hepatectomy plus systemic therapy or systemic therapy alone for BCLM and to determine selection factors to guide surgical therapy.Materials and methodsPatients who underwent hepatectomy plus systemic therapy (n = 136) and systemic therapy alone for isolated BCLM (n = 763) were compared. Overall survival (OS) was analyzed after propensity score matching. Intrinsic subtypes were defined as: luminal A (estrogen receptor [ER]+ and/or progesterone receptor positive [PR]+, human epidermal growth factor receptor 2 [HER2]–), luminal B (ER and/or PR+, HER2+), HER2-enriched (ER and PR–, HER2+), and basal-like (ER, PR, HER2–).ResultsAfter hepatectomy, independent predictors of poor OS were number and size of liver metastases, and intrinsic subtype (hazard ratios, 1.11, 1.16, and 4.28, respectively). Median OS was 75 and 81 months among patients with luminal B and HER2-enriched subtypes, compared with 17 and 53 months among patients with basal-like and luminal A subtypes (P < .001). Median progression-free survival (PFS) was 60 months with the HER2-enriched subtype, compared with 17, 16, and 5 months with luminal A, luminal B, and basal-like subtypes, respectively (P < .001). After propensity score matching, 5-year OS rates were 56% vs. 40% in the surgery vs. systemic therapy alone groups (P = .018).ConclusionSurgical resection of BCLM yielded higher OS compared with systemic therapy alone and prolonged PFS among patients with the HER2-enriched subtype. These findings support the use of surgical therapy in appropriately selected patients, based on intrinsic subtypes.     

不同亚型乳腺癌脑转移临床特点及生存分析

目的探讨不同亚型乳腺癌脑转移的临床特点及预后。方法回顾性分析90例乳腺癌脑转移患者的临床资料,分为雌激素受体(ER)和(或)孕激素受体(PR)阳性,人表皮生长因子受体-2(HER-2)阳性和三阴性(ER、PR及HER-2均阴性)三种亚型。 结果90例患者中,ER和(或)PR阳性51例(56.7%)、HER-2阳性12例(13.3%)、三阴性27例(30.0%),中位无病生存期(30.9月、25.4月和16.0月,P=0.001)、无脑转移生存期(36.0月、38.0月和22.0月,P=0.008)之间差异有统计学意义,但总生存期(52.0月、25.5月和36.0月,P=0.075)及确诊脑转移后的生存期(11.0月、5.5月和8.0月,P=0.829)之间的差异无统计学意义。结论三阴性乳腺癌无病生存期明显缩短,更易于早期发生脑转移,但总生存期及确诊脑转移以后的生存期无明显差别。     

The effect of tumor subtype on the time from primary diagnosis to development of brain metastases and survival in patients with breast cancer

Our group has previously published the Diagnosis-Specific Graded Prognostic Assessment (GPA) showing the prognostic factors associated with survival in patients with brain metastases (BM). The purpose of this study is to investigate the relationship of breast cancer subtype to the time interval from primary diagnosis (PD) to development of BM (TPDBM), number of BM at initial BM presentation and survival. We analyzed our previously described multi-institutional retrospective database of 865 breast cancer patients treated for newly-diagnosed BM from 1993 to 2010. Several factors found to be associated with survival were incorporated into the Breast-GPA, including tumor subtype. The GPA database was further analyzed to determine if the subtype correlated with the TPDBM, number of BM, and survival from PD. After exclusions for incomplete data, 383 patients remained eligible for analysis. The subtypes were approximated as follows: Luminal B: triple positive; HER2: HER2 positive/ER/PR negative; Luminal A; ER/PR positive/HER2 negative; Basal: triple negative. Patients with Basal (90), HER2 (119), Luminal B (98) and Luminal A (76) tumor subtypes had a median TPDBM of 27.5, 35.8, 47.4 and 54.4 months (p < 0.01), median survival from PD of 39.6, 66.4, 90.3 and 72.7 months (p < 0.01) and median survival from BM of 7.3, 17.9, 22.9 and 10.0 months (p < 0.01), respectively. Tumor subtype is an important prognostic factor for survival in patients with breast cancer and BM. Although TPDBM is not an independent prognostic factor for survival (and thus not part of the Breast-GPA), the TPDBM does correlate with tumor subtype but does not correlate with the number of BM. Patients with Basal and HER2 tumor subtypes have short TPDBM. Prospective studies are needed to determine if screening brain MRIs are indicated in patients with Basal or HER2 subtypes.     

Correlation between Ki67 and Histological Grade in Breast Cancer Patients Treated with Preoperative Chemotherapy

Background and Aim: Breast cancer (BC) is a heterogeneous disease and cell proliferation markers may helpto identify subtypes of clinical interest. We here analyzed the correlation between cell proliferation determinedby Ki67 and HG in BC patients undergoing preoperative chemotherapy (PCT). Materials and Methods: Weobtained clinical/pathological data from patients with invasive BC treated at our institution from 1999 until2012. Expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor type2 (HER2) and Ki67 were determined by immuno-histochemistry (IHC). Clinicopathological subtypes weredefined as: Luminal A, ER and/or PR positive, HER2 negative, HG 1 or 2; Luminal B, ER and/or PR positive,HER2 negative or positive and/or HG 3; triple negative (TN), ER, PR and HER2 negative independent ofHG; HER2 positive, ER, PR negative and HER2 positive, independent of HG. By using Ki67, a value of 14%separated Luminal A and B tumors, independently of the histological grade. We analyzed correlations betweenKi67 and HG, to define BC subtypes and their predictive value for response to PCT. Results: 1,560 BC patientswere treated in the period, 147 receiving PCT (9.5%). Some 57 had sufficient clinicopathological information tobe included in the study. Median age was 52 years (26-72), with 87.7% invasive ductal carcinomas (n=50). Weperformed IHC for Ki67 in 40 core biopsies and 50 surgical biopsies, 37 paired samples with Ki67 before andafter chemotherapy being available. There was no significant correlation between Ki67 and HG (p=0.237), bothcategorizing patients into different subtypes. In most cases Ki67 decreased after PCT (65.8%). Only 3 patientshad pathologic complete response (cPR). Conclusions: In our experience we did not find associations betweenKi67 and HG. Determination of clinicopathological luminal subtypes differs by using Ki67 or HG.     

Implications of constructed biologic subtype and its relationship to locoregional recurrence following mastectomy

Introduction

We examined the prognostic value of biologic subtype on locoregional recurrence (LRR) after mastectomy in a cohort of low risk women who did not receive adjuvant radiation therapy.

Methods

A total of 819 patients with invasive breast cancer underwent mastectomy from January 2000 through December 2005. No patient received preoperative chemotherapy. Estrogen receptor (ER) receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status were used to construct the following 4 subtypes: i) ER+ or PR+ and HER2- (HR+/HER2-), ii) ER+ or PR+ and HER2+ (HR+/HER2+), iii) ER- and PR- and HER2+ (HR-/HER2+)and iv) ER- and PR- and HER2- (HR-/HER2-). LRR-free survival was estimated by the Kaplan-Meier method. Cox proportional hazard models were used to evaluate the association between time-to-event outcomes and patient prognostic factors.

Results

At a median follow-up of 58 months, five-year cumulative incidence of LRR for the entire cohort was 2.5%. Subtype specific LRR rates were 1% for HR+/HER2-, 6.5% in HR+/HER2+, 2% for HR-/HER2+ and 10.9% for HR-/HER2- (P < 0.01). In HER-2+ patients (irrespective of ER/PR status), trastuzumab therapy was not associated with LRR-free survival. On multivariate analysis, one to three positive lymph nodes (HR 4.75 (confidence interval (CI) 1.75 to 12.88, P < 0.01), ?? 4 positive lymph nodes (HR23.4 (CI 4.64 to 117.94, P < 0.01), HR+/HER2+ (HR 4.26 (CI 1.05 to 17.33), P = 0.04), and HR-/HER2- phenotype (HR 13.87 (CI 4.96 to 38.80), P < 0.01) were associated with shorter LRR-free survival whereas age > 50 at diagnosis (HR 0.31 (CI 0.12 to 0.80), P = 0.02) was associated with improved LRR-free survival. Among the HR-/HER2- subtypes, five-year LRR incidence was 23.4% in patients with positive lymph nodes compared to 7.8% for lymph node negative patients (P = 0.01), although this association did not reach significance when the analysis was limited to HR-/HER2- women with only one to three positive lymph nodes (15.6% versus 7.8%, P = 0.11).

Conclusions

Constructed subtype is a prognostic factor for LRR after mastectomy among low risk women not receiving adjuvant radiation therapy, although rates of LRR remain low across subtypes. Patients with node positive, HR-/HER2- type tumors were more likely to experience LRR following mastectomy alone. Prospective studies to further investigate the potential benefit of adjuvant radiation therapy in these women are warranted.     

Gemcitabine and carboplatin for pretreated metastatic breast cancer: the predictive value of immunohistochemically defined subtypes

Background

We evaluated the efficacy of gemcitabine and carboplatin for patients affected by pretreated metastatic breast cancer. A subgroup analysis was performed to evaluate the predictive value of immunohistochemically defined breast cancer subtypes.

Methods

We included human epidermal growth factor 2 (HER-2) negative metastatic breast cancer resistant to previous anthracycline-based and taxane-based chemotherapy, and HER-2 positive metastatic breast cancer with at least two progressions of disease during protracted trastuzumab-based therapy. Treatment consisted of gemcitabine (1000 mg/m² intravenous (iv) on days 1 and 8) and carboplatin (area under the curve 5 iv on day 1) applied every 3 weeks.

Results

Forty-two patients were registered. Disease control was 58%, with a median time-to-progression (TTP) of 7 months (range 1–12) and a median overall survival of 10.5 months (range 1–34). Patients were grouped as triple negative (ER and PR negative, HER-2 negative), HER-2 (HER-2 positive, ER and PR negative), luminal B (ER and/or PR positive and either HER-2 positive and/or high Ki67), and luminal A (ER and/or PR positive and HER-2 negative and low Ki67). For luminal A patients, disease control was lower (luminal A 34 vs. others 67%; P = 0.02), TTP was shorter (luminal A 2.4 months vs. others 6.3 months, P = 0.015), and overall survival was shorter (luminal A 7.5 months vs. others 11.7 months, P = 0.034) than for other subtypes.

Conclusions

Gemcitabine and carboplatin are effective for pretreated patients with metastatic breast cancer. Luminal A subtype seems to fare poorly compared with other subtypes. Specific difference in gene expression might account for the different outcome.     

Does the subtype of breast cancer affect the diagnostic performance of axillary ultrasound for nodal staging in breast cancer patients?

IntroductionImaging findings can be affected by histopathological characteristics, such as breast cancer subtypes. The aim was to determine whether the diagnostic performance, in particular negative predictive value (NPV), of axillary US differs per subtype of breast cancer.MethodsAll patients diagnosed between 2008 and 2016 in our hospital with primary invasive breast cancer and an axillary US prior to axillary surgery were included. Histopathology of axillary surgery specimens served as gold standard. The NPV, sensitivity, specificity, positive predictive value (PPV) and accuracy of the axillary US were determined for the overall population and for each subtype (ER+/PR+HER2-,HER2+, triple negative tumors). The Chi-square test was used to determine the difference in diagnostic performance parameters between the subtypes.ResultsA total of 1094 breast cancer patients were included. Of these, 35 were diagnosed with bilateral breast cancer, resulting in 1129 cancer cases. Most common subtype was ER+/PR+HER2- in 858 cases (76.0%), followed by 150 cases of HER2+ tumors (13.3%) and 121 cases of triple negative tumors (10.7%). Sensitivity, specificity and accuracy of axillary US did not significantly differ between the subtypes. There was a significant difference for NPV between triple negative tumors and HER2+ tumors (90.3% vs. 80.2%, p = 0.05) and between HER2+ and ER/PR+HER2- tumors (80.2% vs. 87.2%, p = 0.04).ConclusionThere was no significant difference in the diagnostic performance of axillary US between the subtypes, except for NPV. This was highest in triple negative subtype and lowest in HER2+ tumors. This can be explained by the difference in prevalence of axillary lymph node metastases in our cohort.     

Clinicopathologic features,patterns of recurrence,and survival among women with triple‐negative breast cancer in the National Comprehensive Cancer Network

BACKGROUND:

The objective of this study was to describe clinicopathologic features, patterns of recurrence, and survival according to breast cancer subtype with a focus on triple‐negative tumors.

METHODS:

In total, 15,204 women were evaluated who presented to National Comprehensive Cancer Network centers with stage I through III breast cancer between January 2000 and December 2006. Tumors were classified as positive for estrogen receptor (ER) and/or progesterone receptor (PR) (hormone receptor [HR]‐positive) and negative for human epidermal growth factor receptor 2 (HER2); positive for HER2 and any ER or PR status (HER2‐positive); or negative for ER, PR, and HER2 (triple‐negative).

RESULTS:

Subtype distribution was triple‐negative in 17% of women (n = 2569), HER2‐positive in 17% of women (n = 2602), and HR‐positive/HER2‐negative in 66% of women (n = 10,033). The triple‐negative subtype was more frequent in African Americans compared with Caucasians (adjusted odds ratio, 1.98; P < .0001). Premenopausal women, but not postmenopausal women, with high body mass index had an increased likelihood of having the triple‐negative subtype (P = .02). Women with triple‐negative cancers were less likely to present on the basis of an abnormal screening mammogram (29% vs 48%; P < .0001) and were more likely to present with higher tumor classification, but they were less likely to have lymph node involvement. Relative to HR‐positive/HER2‐negative tumors, triple‐negative tumors were associated with a greater risk of brain or lung metastases; and women with triple‐negative tumors had worse breast cancer‐specific and overall survival, even after adjusting for age, disease stage, race, tumor grade, and receipt of adjuvant chemotherapy (overall survival: adjusted hazard ratio, 2.72; 95% confidence interval, 2.39‐3.10; P < .0001). The difference in the risk of death by subtype was most dramatic within the first 2 years after diagnosis (overall survival for 0‐2 years: OR, 6.10; 95% confidence interval, 4.81‐7.74).

CONCLUSIONS:

Triple‐negative tumors were associated with unique risk factors and worse outcomes compared with HR‐positive/HER2‐negative tumors. Cancer 2012. © 2012 American Cancer Society.     

HER-2/neu Status: A Neglected Marker of Prognostication and Management of Breast Cancer Patients in India

Background: Categorizing breast tumors based on the ER, PR and HER/Neu 2 receptor status is necessary in order to predict outcome and assist in management of breast cancer. Herfe we assessed this question in South Indian patients. Materials and Methods: A total of 619 formalin fixed paraffin embedded breast tumor tissues were collected from pathology archives after receipt of ethical clearance. With the help of primary and secondary conjugated antibodies, expression status of ER, PR and HER2/neu was determined. All the experimental data were assessed for correlations with histopathological features of tumors and clinical presentation of the subjects. Results: In the present study, the ages ranged from 20-87 years with a mean of 50.0±12.q years, and majority of the tumors (84%) were of infiltrating duct cell carcinoma type. Assessment of ER, PR and Her-2/neu expression showed that 46% were triple negative. Interestingly, an inverse relation between ER, PR and HER-2/neu was apparent in 41.2% (p<0.0001) of the tumors, of which 24.5% (p<0.0001) were ER and PR co-negative but HER-2 positive. Conclusions: ER and PR positive tumors are less common (i.e<30%) compared to HER-2/neu positive tumors (i.e>50%) in Indian breast cancer patients, underlining the need for effective diagnostic screening and specific therapeutic managements in order to improve the survival rate of patients in low resource countries such as India.     

Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial

IntroductionPotential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1–3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC).MethodsIn a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459).ResultsConcordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients.ConclusionIn the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone.Trial registrationThe WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.