HR+/HER2-乳腺癌新辅助治疗及疗效预测指标研究进展#br#

激素受体阳性/人表皮生长因子受体 2 阴性(HR+/HER2-)乳腺癌对辅助化疗疗效尚不理想,而将新辅助疗法应用于局部晚期乳腺癌已成为一种安全有效的方案。但新辅助治疗的最佳治疗方案仍存在诸多争议,对于新辅助治疗的预测因子的价值和临床应用前景尚不明确。新辅助方案之间的联合应用是否进一步增加疗效,目前仍有争论。新辅助治疗在HR+/HER2-乳腺癌中的应用及预测相关指标具有很好的前景。该文根据最新研究成果,从新辅助化疗方案、新辅助内分泌与新辅助化疗的比较、新辅助化疗联合新辅助内分泌治疗,CDK4/6抑制剂联合内分泌治疗、新辅助治疗各疗效预测指标等方面进行综述。     

The HER2 extracellular domain as a prognostic and predictive factor in breast cancer

The HER2/neu proto-oncogene encodes a 185-kd transmembrane receptor with tyrosine kinase activity. Amplification of HER2 with overexpression of the p185HER2 receptor occurs in 20%-30% of breast cancers and has been established as an independent prognostic factor in numerous studies. Increasing evidence suggests that HER2 may be a predictive marker for response to chemotherapy and hormonal therapy. HER2 overexpression has provided a new target in breast cancer therapy, as evidenced by the development of trastuzumab (Herceptin(R)), a monoclonal antibody targeted against HER2. Detection of HER2 in the clinical setting is performed by immunohistochemistry or fluorescence in situ hybridization in tissue, and by detection of the shed extracellular domain in serum or plasma. Differences in methodology, reagents, and scoring systems have led to varying results in different patient cohorts, contributing to the debate on the role of HER2 as a prognostic and predictive factor. This review focuses on the prognostic and predictive value of serum HER2 detection in the management of HER2-positive breast cancer.     

Combined analysis of receptor expression reflects inter-and intra-tumor heterogeneity in HR+/HER2+ breast cancer

Breast Cancer Research and Treatment - Hormone receptor-positive and human epidermal growth factor receptor 2-positive (HR+/HER2+ breast cancer comprise approximately 5–10% of all invasive...     

Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression

BackgroundTaxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1–3 positive lymph nodes (LNs) only.Patients and methodsA total of 2011 BC patients (18–65 years, pN1) were entered into a randomized phase III trial comparing 4 × E₉₀C₆₀₀ q3w followed by 4 × docetaxel₁₀₀ q3w (n = 1008) with the current standard: 6 × F₅₀₀E₁₀₀C₅₀₀ q3w (n = 828) or C₆₀₀M₄₀F₆₀₀ d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors.ResultsBaseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18–0.82) for EC-Doc versus FEC (test for interaction; P = 0.01).ConclusionEC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1–3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy.Clinical Trial numberClinicalTrials.gov, NCT02115204.     

ER/PR+和HER2-型乳腺癌患者免疫组化指标的列线图预后模型

目的：探讨改良雌激素受体（estrogen receptor,ER)/孕激素受体(progesterone receptor,PR)阳性（+）及人类表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阴性（-）（ER/PR+、HER2-）型乳腺癌患者的传统预后模型,满足目前的临床实际需求。方法：选取了2009 年1 月至2009 年12 月上海市黄浦区中心医院乳腺外科收治的335 例ER/PR+、HER2-型乳腺癌患者。将97 个变量纳入模型,采用SCAD变量选择的方法,在充分考虑协变量是否存在对数线性关系、非对数线性关系（分段线性关系）临界值的合理确定、共线问题后,构建一个新的ER/PR+、HER2-型乳腺癌患者传统免疫组化指标的Cox回归预后模型,并进一步建立其列线图模型;在此基础上建立了术后1、3 和5 年生存概率的列线图;并通过比较模型的区分度（discrimination）和校准度（calibration）来评价模型的预测能力。结果：通过乳腺癌预后建立Cox 回归模型结果显示,患者的预后与组织级别、淋巴结转移、Ki67、PR和年龄等因素有关;其中组织级别和淋巴结转移对风险比的影响呈对数线性关系,Ki67、PR和年龄对风险比的影响呈非对数线性关系,其合理临界值分别为Ki67（60%）、PR（20%）和年龄（55 岁）。该模型术后1、3 和5 年的ROC曲线下面积（AUC值）均高于0.85,说明该Cox 回归模型具有较高的区分度。该模型Gr?nnesby-Borgan 拟合优度检验统计量值为1.37、对应的P值为0.5,说明该Cox回归模型有较好的校准度。结论：通过改良ER/PR+和HER2-型乳腺癌患者的传统预后模型,建立患者术后1、3 和5年生存概率的列线图,能准确、直观、有效地预测患者的生存概率,对乳腺癌患者临床治疗有较好的指导意义。     

Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network

Background:

Adjuvant trastuzumab with chemotherapy is standard treatment for HER2-positive breast cancer, defined as either HER2 IHC3+ or IHC2+ and FISH amplified. The aim of this study was to investigate the degree to which HER2 amplification in terms of HER2 gene copy numbers in HER2+IHC2+ cancers affected the outcome in a community setting.

Methods:

Case records of 311 consecutive patients with early breast cancer presenting between 1st January 2005 and 31st December 2008 were reviewed. Progression-free survival and overall survival were calculated with the Kaplan–Meier method using STATA 13.

Results:

Among 3+ cases (n=230) 163 received T vs 67 no-T. Among 2+ cases (n=81) 59 received T vs 22 no-T. Among 59 IHC2+-treated cases n=28 had an average of >12, n=13 had >6 to <12, and n=18 had >2 to <6 HER2 gene copies, respectively. The time of progression and overall survival of high and low copy number patients was similar and better than the intermediate copy number and the untreated cohorts.

Conclusions:

High HER2 copy number (>12) appears to be associated with consistently better response compared with patients with intermediate HER2 copy numbers (6–12). In light of emerging data of patients showing insensivity to trastuzumab therapy, we propose that the HER2 gene copy number value should be included as an additional indicator for stratifying both the management and the follow-up of breast cancer patients.Trastuzumab is a humanised monoclonal antibody directed at the human epidermal growth factor receptor 2 (HER2), which is overexpressed in ∼15% of newly diagnosed invasive breast cancers (HER2+) (Slamon et al, 1987). Adjuvant trastuzumab, in conjunction with chemotherapy, is now the standard of care for these patients, following the significantly improved outcomes demonstrated in several large multinational clinical trials. (Piccart-Gebhart et al, 2005, Romond et al, 2005, Slamon et al, 2006, Joensuu et al, 2006). A similar magnitude of benefit has been confirmed in a ‘community'' setting in a UK Cancer network (Webster et al, 2012).Accurate diagnosis of HER2+ cancers is important to maximise the benefit of targeted therapy. All breast cancers should now be tested for HER2 expression and two methods are used. Firstly, immunohistochemistry detects HER2 protein expression on the cell membrane, and is described on a scale of 0–3 based on the Hercept Test Score (Dowsett et al, 2003). Thus, scores 0 and 1+ are considered negative, and score 3+, meaning that >30% of invasive tumour cells demonstrate uniform intense membrane staining, considered to be positive. An equivocal result represented by score 2+, requires further tests for confirming the presence or absence of HER2 gene amplification and this is achieved using the second method, in situ hybridisation or most commonly fluorescent in situ hybridisation (FISH). The most recent guidelines produced by the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) (Wolff et al, 2007) define a FISH result of more than six copies of the HER2 gene per nucleus, or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2 as a positive result. A ratio of HER2/CEP17 >2.0 was required to enter the large adjuvant trastuzumab trials, and was approved by the US FDA.Despite the undoubted benefits of trastuzumab relapses do still occur and clearly not all patients derive the same benefit from treatment. HER2 gene amplification in those cancers considered HER2+ is variable and raises the question—does the degree of HER2 amplification influence outcome?To answer this question, researchers have looked to the data sets of the original landmark adjuvant studies. For example, a retrospective analysis of the HERA trial dataset (Dowsett et al, 2009) investigated whether IHC status (2+ vs 3+), the degree of FISH amplification or polysomy of chromosome 17 affected clinical outcome and the conclusion was that there was no evidence for reduced benefit for adjuvant trastuzumab in IHC2+FISH+ cases.This study is a follow on to the previously published South East Wales Network experience (Webster et al, 2012), and our aim was to examine, again in a ‘community'' setting, whether the degree of HER2 positivity affected the outcome of adjuvant treatment.     

The prognostic impact of age in different molecular subtypes of breast cancer

Breast cancer is a heterogeneous entity composed of distinct molecular subgroups with different molecular and clinical features. We analyzed the association between molecular breast cancer subgroups, age at diagnosis, and prognosis in a compilation of publicly available gene expression datasets. Affymetrix gene expression data (U133A or U133Plus2.0 arrays) of 4467 breast cancers from 40 datasets were compiled and homogenized. Breast cancer subgroups were defined based on expression of ESR1, PR, HER2, and Ki67. Event-free survival was calculated as recurrence-free survival or distant metastasis-free survival if recurrence-free survival was not available. Young age at diagnosis is associated with higher frequency of triple negative and HER2 subtypes and lower frequency of luminal A breast cancers. The 5-year event-free survival rates of patients aged less than 40, between 40 and 50, and >50 years were 54.3 ± 3.5, 68.5 ± 1.9, and 70.4 ± 1.3 %, respectively. When controlling for breast cancer subtype, we found that age <40 years remained significantly associated with poor prognosis in triple negative breast cancer. The effect was modest in luminal tumors and not found in HER2 subtype. Both subtypes and age retained their significances in multivariate analysis. Association of age at diagnosis with molecular breast cancer subtype contributes to its important role as prognostic factor among patients with breast cancer. Still, within the group of triple negative breast cancer, young age <40 years has a significant prognostic value which was retained in multivariate analysis.     

Comparison of the prognostic value of genomic grade index,Ki67 expression and mitotic activity index in early node-positive breast cancer patients

BackgroundThe genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial.Patients and methodsThe five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS).ResultsExpected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases.ConclusionsIn this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.     

Expression of truncated HER2 and its prognostic value in HER2-positive breast cancer patients

Purpose

The purpose of this work was to assess the truncated form of human epidermal growth factor receptor 2 (HER2) such as p95-HER2 expression in HER2-positive breast cancer (BC) patients who developed metastatic disease after adjuvant treatment with a trastuzumab-containing regimen.

Stage IV breast cancer: a population‐based study about prognostic factors according to HER2 and HR status

We aim to describe trends in net survival (NS) and to assess the prognostic factors among women with de novo metastatic breast cancer (MBC) according to human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status. Data on women suffering from de novo MBC and diagnosed from 1998 to 2009 were provided by the Côte‐d'Or breast cancer registry. NS was described using the Pohar Perme estimator and prognostic factors were investigated in a generalised linear model. We identified 232 patients (mean age = 64.7). Median NS was 29.2 months, 1‐ and 5‐year NS were 76% and 26% respectively. The survival trend in patients with HER2‐positive tumours who did not receive trastuzumab was similar to that in women with triple‐negative tumours. A higher relative excess risk of death by cancer was observed for high‐grade tumours [RER, relative excess rates = 1.76 (95% CI, confidence intervals: 1.17–2.62) for Scarff Bloom Richardson grade 3 vs. 1 + 2], while a lower risk was observed for luminal tumours [RER = 0.49 (95% CI: 0.27–0.89)] and HER2‐positive tumours treated with trastuzumab [RER = 0.28 (95% CI: 0.14–0.59)], both compared with triple‐negative tumours. Surgery of the primary tumour was associated with better survival [RER = 0.43 (95% CI: 0.28–0.68)]. With half of the women dead before 29 months, stage IV breast cancer still has a bleak outlook. Progress should continue with new target therapies for both HR and HER2 receptors.     

The implementation of CDK 4/6 inhibitors and its impact on treatment choices in HR+/HER2− advanced breast cancer patients: A study of the Dutch SONABRE Registry

In August 2017, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have been reimbursed in the Netherlands for patients with hormone receptor positive (HR+), HER2 negative (HER2?) advanced breast cancer (ABC). This study evaluates the implementation of CDK4/6 inhibitors and changes in treatment choices in the Netherlands. All patients diagnosed with HR+/HER2? ABC in 2009 to 2018 in seven hospitals were selected from the Southeast Netherlands Advanced Breast cancer (SONABRE) registry. The 2-year cumulative use of CDK4/6 inhibitors since reimbursement date (August 2017) was assessed using competing-risk methodology in two cohorts. The first cohort included patients with ABC diagnosis between August 2017 and December 2018. The second cohort included patients with ABC diagnosis between 2009 and August 2017, and still alive on August 1, 2017. In addition, treatment choices in the first three lines of therapy in calendar years 2009 to 2018 were evaluated for the total study population. Among patients diagnosed since August 2017 (n = 214), 50% (95% confidence interval [CI] = 43-57) received CDK4/6 inhibitors within 2 years beyond diagnosis. Of eligible patients diagnosed before August 2017 (n = 417), 31% (95% CI = 27-36) received CDK4/6 inhibitors within 2 years following reimbursement. Another 20% of both cohorts are still CDK4/6 inhibitor naïve and on first-line therapy. The use of chemotherapy decreased in first two lines of therapy between 2009 and 2018 (first-line: 29%-13%; second-line: 26%-19%). The implementation rate of CDK4/6 inhibitors since reimbursement is currently 50% within 2 years beyond diagnosis and is expected to increase further. The implementation of targeted therapy decreased the use of chemotherapy as first-line therapy.     

Clinical utility of the IHC4+C score in oestrogen receptor-positive early breast cancer: a prospective decision impact study

Background:

Most oestrogen receptor (ER)-positive early breast cancer diagnosed today is highly curable with multimodality treatment. Systemic adjuvant treatments including endocrine therapy and chemotherapy have made a significant contribution to the increasing cure rates over the past three decades. However not all women will require chemotherapy. The IHC4+C score is a prognostic tool that integrates four immunohistochemical measures with clinicopathological features to estimate the residual risk of distant recurrence at 10 years in post-menopausal women with ER-positive breast cancer who have received 5 years of endocrine therapy. Retrospective studies indicate that the test can identify a set of women that are at such low risk of recurrence that chemotherapy can be of little benefit.

Methods:

In this study, 124 patients were prospectively selected from the multidisciplinary team meeting between January 2013 and April 2014 for IHC4+C testing. Adjuvant systemic treatment recommendations by clinicians were recorded without and with the availability of the score in addition to the patient''s decision.

Results:

There was concordance in the MDT''s recommendation without and with the availability of the score in 73% of cases. Clinicians recommended chemotherapy or at least its discussion to 74 (59%) patients, which fell to 32 (34%) patients after the IHC4+C score was made available, sparing one in four tested patients a chemotherapy recommendation, along with its toxicity and expense.

Conclusion:

This decision impact study shows that when used by clinicians in the multidisciplinary team meeting for adjuvant decision-making, a significant proportion of patients are spared chemotherapy recommendations.     

The localization of HER4 intracellular domain and expression of its alternately-spliced isoforms have prognostic significance in ER+ HER2- breast cancer

Human epidermal growth factor receptors (HERs) are known to play a pivotal role in breast cancer, both as prognostic markers and as therapeutic targets. The importance of Her4 expression is, however, still controversially discussed; there are few reports on the clinical significance of HER4, its splice variants, and cleaved HER4 intracellular domains (4ICD) which function differently depending on their localization in breast cancer. In 238 primary invasive breast cancer patients, we analyzed the expression levels of HER4 extracellular (JM-a and JM-b) and intracellular (CYT-1 and CYT-2) domains as well as 4ICD localization, and tested the relationship with clinicopathological characteristics and prognosis. The predominantly-expressed extracellular domain was JM-a, and lower CYT-2 dominance was a factor related to better relapse-free survival. CYT-2-dominance with higher nuclear 4ICD expression was a favorable prognostic marker especially in patients with the ER+ HER2- subtype treated with endocrine therapy. The absence of cytoplasmic 4ICD staining was related to better prognosis in CYT-1-dominant patients. In conclusion, analysis of splicing variants and 4ICD localization should be considered when targeting HER4 as a novel ER+/HER2- breast cancer treatment.     

Genetic heterogeneity of HER2 in breast cancer: impact on HER2 testing and its clinicopathologic significance

In 2009, ASCO/CAP expanded its human epidermal growth factor receptor type 2 (HER2) testing guideline to define HER2 genetic heterogeneity (GH). However, the clinical significance of GH is unclear. We investigated the impact of HER2 GH on HER2 testing and studied its clinicopathologic significance. Paraffin-embedded tumor tissues of surgical resections of 617 non-consecutive breast carcinoma patients were studied by routine HER2 fluorescence in situ hybridization (FISH). HER2 GH was evaluated, and the results were correlated with HER2 protein expression by immunohistochemistry and HER2 gene amplification by FISH, and with various clinicopathologic parameters. HER2 GH was observed in 15.2 % (94/617) of the patients. It was associated with low-to-middle level of HER2 expression, and with none-to-low level of HER2 gene amplification. Among the 17 patients with equivocal HER2 FISH results, 35.3 % (6/17) of tumors displayed GH. In contrast with HER2-positive tumors without GH, tumors with HER2 GH demonstrated significant association with lower histologic grade, smaller tumor size, and proclivity to hormone receptor expression. HER2 GH is a substantial cause of equivocal HER2 testing results of breast cancer by FISH. Tumors with HER2 GH showed that biologic features resemble more of HER2-negative tumors than HER2-positive tumors without GH. The findings indicate a need of the guidelines to clarify whether tumors with HER2 GH truly benefit from HER2-targeted therapy of breast cancer.