The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase

Background

The MINDACT (Microarray In Node-negative and 1-3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included.

Methods

MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen → letrozole are offered.

Results

During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7-11.8%; P < .0001). Compliance with the treatment decision was high (>92%).

Conclusions

The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses.     

Characterisation of multifocal breast cancer using the 70-gene signature in clinical low-risk patients enrolled in the EORTC 10041/BIG 03-04 MINDACT trial

BackgroundIn multifocal breast cancer, guidelines recommend basing adjuvant systemic treatment decisions on characteristics of the largest lesion, disregarding multifocality as an independent prognosticator. We assessed the association between multifocal disease and both the 70-gene signature (70-GS), and distant metastasis-free survival (DMFS) in clinical low-risk breast cancer patients enrolled in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy (MINDACT) trial.Patients and methodsThe analysed population consisted of enrolled patients in the MINDACT trial with clinical low-risk disease, defined by a modified Adjuvant! Online cut-off for the 10-year risk of recurrent disease or death. Eligibility criteria of MINDACT dictate that patients with multifocal disease could be included if the different lesions had similar pathological characteristics. The presence of multifocal disease was deducted from the case report form (CRF)-question for sum of diameter for all invasive tumour foci. Clinicopathological characteristics and gene expression of patients with unifocal and multifocal (largest lesion) disease were compared. Subsequently, the association between multifocal disease and the 70-GS was evaluated as well as the association between multifocality and 5-year DMFS.ResultsThe study included 3090 clinical low-risk patients with unifocal and 238 patients with multifocal disease. Apart from a higher prevalence of lobular tumours (21.8% versus 10.8%, by local pathology), we did not observe differences in baseline characteristics between multifocal and unifocal tumours. Patients with multifocal tumours were more likely to be at high genomic risk as compared to patients with unifocal tumours (22.7% versus 17.3%, odds ratio [OR] 1.45, 95% confidence interval [CI] 1.02–2.07, P = 0.038). We did not find a significant association between tumour focality and DMFS (97.1% for unifocal versus 96.9% for multifocal, hazard ratio [HR] = 1.55, 95% CI 0.68–3.46, P = 0.172), nor a signal for a potential interaction between the prognostic effect of the 70-GS and focality of the tumour regarding DMFS.ConclusionIn the group of clinical low-risk MINDACT patients, multifocal tumours were more likely to have a high-risk 70-GS profile compared to unifocal tumours. We did not observe a significant interaction between multifocality and the 70-GS with respect to survival without distant metastasis in these patients.     

高通量基因检测系统MammaPrint与乳腺癌预后预测

化疗是乳腺癌患者术后最重要的辅助治疗手段.由于传统的临床病理指标不能准确预测患者复发风险,因此不能准确筛选出哪些患者需要化疗、哪些患者不需要化疗.高通量基因检测系统MammaPrint已被证实可较准确预测相当一部分乳腺癌患者复发风险,因而可用于指导个体化治疗.本文就MammaPrint的临床应用及研究现状作一综述.     

Risk estimations and treatment decisions in early stage breast cancer: Agreement among oncologists and the impact of the 70-gene signature

BackgroundClinical decision-making in patients with early stage breast cancer requires adequate risk estimation by medical oncologists. This survey evaluates the agreement among oncologists on risk estimations and adjuvant systemic treatment (AST) decisions and the impact of adding the 70-gene signature to known clinico-pathological factors.MethodsTwelve medical oncologists assessed 37 breast cancer cases (cT1–3N0M0) and estimated their risk of recurrence (high or low) and gave a recommendation for AST. Cases were presented in two written questionnaires sent 4 weeks apart. Only the second questionnaire included the 70-gene signature result.ResultsThe level of agreement among oncologists in risk estimation (κ = 0.57) and AST recommendation (κ = 0.57) was ‘moderate’ in the first questionnaire. Adding the 70-gene signature result significantly increased the agreement in risk estimation to ‘substantial’ (κ = 0.61), while agreement in AST recommendations remained ‘moderate’ (κ = 0.56). Overall, the proportion of high risk was reduced with 7.4% (range: 6.9–22.9%; p < 0.001) and the proportion of chemotherapy that was recommended was reduced with 12.2% (range: 5.4–29.5%; p < 0.001).ConclusionOncologists’ risk estimations and AST recommendations vary greatly. Even though the number of participating oncologists is low, our results underline the need for a better standardisation tool in clinical decision-making, in which integration of the 70-gene signature may be helpful in certain subgroups to provide patients with individualised, but standardised treatment.     

Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial

Background and purpose

We conducted a prospective phase II multicentric trial to determine if radical radiation therapy to all metastatic sites might improve the progression-free survival (PFS) in oligometastatic breast cancer patients. Secondary endpoints were local control (LC), overall survival (OS) and toxicity.

Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial

This Review describes the work conducted by the TRANSBIG consortium in the development of the MINDACT (Microarray In Node negative Disease may Avoid ChemoTherapy) trial. The goal of the trial is to provide definitive evidence regarding the clinical relevance of the 70-gene prognosis signature, and to assess the performance of this signature compared with that of traditional prognostic indicators for assigning adjuvant chemotherapy to patients with node-negative breast cancer. We outline the background work and the key questions in node-negative early-stage breast cancer, and then focus on the MINDACT trial design and statistical considerations. The challenges inherent in this trial in terms of logistics, implementation and interpretation of the results are also discussed. We hope that this article will trigger further discussion about the difficulties of setting up and analyzing trials aimed at establishing the worth of new methods for better selection of patients for cancer treatment.     

Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819

The role of cetuximab in the treatment of advanced non-small cell lung cancer (NSCLC) is currently unclear. The molecular target of cetuximab, epidermal growth factor receptor (EGFR), as measured by FISH, has shown potential as a predictive biomarker for cetuximab efficacy in NSCLC. SWOG S0819 is a phase III trial evaluating both the value of cetuximab in this setting and EGFR FISH as a predictive biomarker. This work describes the decision process for determining the design and interim monitoring plan for S0819. Six possible designs were evaluated in terms of their properties and the hypotheses that can be addressed within the design constraints. A subgroup-focused, multiple-hypothesis design was selected for S0819 that incorporates coprimary endpoints to assess cetuximab in both the overall study population and among EGFR FISH-positive (FISH(+)) patients, with the sample size determined based on evaluation in the EGFR FISH(+) group. The chosen interim monitoring plan specifies interim evaluations of both efficacy and futility in the EGFR FISH(+) group alone. The futility-monitoring plan to determine early stopping in the EGFR FISH-nonpositive group is based on evaluation within the positive group, the entire study population, and the nonpositive group. SWOG S0819 uses a design that addresses both the biomarker-driven and general-efficacy objectives of this study.     

Evaluation of acute skin toxicity of breast radiotherapy using thermography: Results of a prospective single-centre trial

Purpose

Radiotherapy is a common adjuvant treatment of breast cancer. Acute radiation-induced dermatitis is a frequent side effect. We hypothesized whether it is possible to capture the increase of local temperature as a surrogate of the inflammatory state induced by radiotherapy. We designed a prospective, observational, single-centre study to acquire data on temperature rise in the treated breast during the course of radiotherapy, establish a possible association with the occurrence of dermatitis and investigate the predictive value of temperature increase in future occurrences of radiation-induced dermatitis.

Liquid biopsy-based clinical research in early breast cancer: The EORTC 90091-10093 Treat CTC trial

There is increasing evidence that breast cancer evolves over time under the selection pressure of systemic treatment. Today, treatment decisions in early breast cancer are based on primary tumour characteristics without considering the disease evolution. Chemoresistant micrometastatic disease is poorly characterised and thus it is not used in current clinical practice as a tool to personalise treatment approaches. The detection of chemoresistant circulating tumour cells (CTCs) has been shown to be associated with worse prognosis in early breast cancer. The ongoing Treat CTC trial is the first international, liquid biopsy-based trial evaluating the concept of targeting chemoresistant minimal residual disease: detection of CTCs following adjuvant chemotherapy (adjuvant cohort) or neoadjuvant chemotherapy in patients who did not achieve pathological complete response (neoadjuvant cohort). This article presents the rational and design of this trial and the results of the pilot phase after 350 patients have been screened and provides insights that might provide information for future trials using the liquid biopsy approach as a tool towards precision medicine (NCT01548677).     

A 38-gene expression signature to predict metastasis risk in node-positive breast cancer after systemic adjuvant chemotherapy: a genomic substudy of PACS01 clinical trial

Currently, no prognostic gene-expression signature (GES) established from node-positive breast cancer cohorts, able to predict evolution after systemic adjuvant chemotherapy, exists. Gene-expression profiles of 252 node-positive breast cancer patients (median follow-up: 7.7 years), mostly included in a randomized clinical trial (PACS01), receiving systemic adjuvant regimen, were determined by means of cDNA custom array. In the training cohort, we established a GES composed of 38 genes (38-GES) for the purpose of predicting metastasis-free survival. The 38-GES yielded unadjusted hazard ratio (HR) of 4.86 (95% confidence interval = 2.76–8.56). Even when adjusted with the best two clinicopathological prognostic indexes: Nottingham prognostic index (NPI) and Adjuvant!, 38-GES HRs were 3.30 (1.81–5.99) and 3.40 (1.85–6.24), respectively. Furthermore, 38-GES improved NPI and Adjuvant! classification. In particular, NPI intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 6.97 [2.51–19.36]). Similarly, Adjuvant! intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 4.34 [1.64–11.48]). The 38-GES was validated on gene-expression datasets from three external node-positive breast cancer subcohorts (n = 224) generated from different microarray platforms, with HR = 2.95 (1.74–5.01). Moreover, 38-GES showed prognostic performance in supplementary cohorts with different lymph-node status and endpoints (1,040 new patients). The 38-GES represents a robust tool able to type systemic adjuvant treated node-positive patients at high risk of metastatic relapse, and is especially powerful to refine NPI and Adjuvant! classification for those patients.     

中国乳腺癌保乳治疗的前瞻性多中心研究

目的 探讨早期乳腺癌保乳治疗的可行性,以及我国开展保乳综合治疗的模式。方法 中国医学科学院中国协和医科大学肿瘤医院等全国共10家三级甲等医院协作,进行早期乳腺癌保乳治疗与切除乳房治疗的大样本前瞻性多中心对照研究。结果 完成保乳手术872例,占符合保乳治疗条件乳腺癌患者的19．5％,占同期全部可手术乳腺癌患者的9．0％。保乳治疗组复发9例（1．0％）,远处转移11例（1．3％）,死亡1例（0．1％）;切除乳房组复发18例（0．5％）,远处转移49例（1．4％）,死亡4例（0．1％）。两组术后局部复发率、远处转移率与死亡率差异无统计学意义（P均〉0．05）。保乳治疗乳房美容效果评估优、良者术后6个月占89．7％,术后1年占91．1％,术后2年占86．6％。结论 保乳治疗在中国是可行的,对早期乳腺癌患者的生存率、复发率无负面影响,提高了患者的生活质量。保乳治疗必须严格把握手术适应证,需要多学科的有机配合,综合治疗是保乳治疗成功的保证。     

Oncotype DX 21基因检测在ER阳性早期乳腺癌中的应用

在诸多评估雌激素受体(estrogen receptor,ER)阳性早期乳腺癌复发风险的多基因工具中,Oncotype DX 21基因检测因其独特的疗效预测作用而被广泛应用于淋巴结阴性患者.多项回顾性研究已证明其在淋巴结阳性人群同样具有预后预测价值,但前瞻性临床试验证据仍不充分.该检测能协同其他重要临床病理因素,影响乳腺癌患者的辅助治疗方案,且具较高的成本效益.该研究就21基因检测对早期乳腺癌患者的预后预测价值、独特优势、辅助治疗决策影响、成本效果和现存争议进行综述.     

Omission of radiotherapy in elderly patients with early breast cancer: 15-Year results of a prospective non-randomised trial

BackgroundWhether radiotherapy (RT) is beneficial in elderly (⩾70 years) patients undergoing conservative surgery for early breast cancer has long been controversial. Recent randomised trials show that most elderly patients do not benefit from RT. We started a prospective non-randomised trial to address this issue in 1987 and now present results for the 627 consecutive pT1/2cN0 patients recruited, and treated by conservative surgery (quadrantectomy) and tamoxifen, and assigned non-randomly to RT or no RT.MethodsWe used multivariate competing risks models to estimate 15-crude cumulative incidence (CCI) of ipsilateral breast tumour recurrence (IBTR), distant metastasis and breast cancer mortality. The models incorporated a propensity score as a measure of probability of receiving RT based on baseline characteristics, to account for the lack of randomisation.ResultsFor pT1 patients, 15-year CCIs of IBTR, distant metastasis and breast cancer death were indistinguishable in the RT and no RT groups. For pT2 patients, 15-year CCI of IBTR was much higher in those not given RT (14.6% versus 0.8%, p = 0.004), although breast cancer mortality and distant metastasis did not differ significantly between RT and no RT.ConclusionsConsistent with the findings of recent randomised trials, our long-term data indicate that most elderly, ER-positive patients with pT1 cN0 breast cancer treated by quadrantectomy do not benefit from RT. The 14.6% CCI of IBTR in our pT2 patients is an additional finding not presented in the trials and suggests that RT should be administered to elderly patients with pT2 disease.     

The impact of sharing results of a randomized breast cancer clinical trial with study participants

Background There has been growing interest in providing clinical trial participants with study results yet only limited information exists regarding the process and impact of sharing results. We sought to evaluate patient perceptions of how results had been shared from a large randomized cooperative group trial, and the impact of learning results. Patients and methods A subset of women who participated in NCCTG 9831 (A Phase III Trial of Adjuvant Chemotherapy with or without Trastuzumab for Women with HER2-positive Breast Cancer) were mailed surveys after the preliminary study results were released to the public and mailed to participants. Results One hundred and 67 of 228 surveys sent (73%) were returned; 61% reported receiving trastuzumab on study; 4% reported recurrent disease. Ninety-five percent of participants were glad they received results; 81% were satisfied with how results were shared; 23% were more anxious after learning the results. Sixty-nine percent correctly interpreted the results. Logistic regression revealed that satisfaction with the process of receiving results was associated with satisfaction with treatment (P = 0.04), and increased anxiety was associated with dissatisfaction with treatment (0.02), incorrect interpretation of results (0.04), and not having received trastuzumab (P < 0.0001). Conclusion Sharing results directly with study participants is met with overwhelmingly favorable responses from patients, although some may not initially understand the findings. The potential for increased anxiety should be considered, and psychosocial support may be required by some. A plan to share results should be routinely and prospectively considered in the design of cancer clinical trials.     

A trial of a self‐assessment tool of problems following treatment of colorectal cancer: a prospective study in Australia primary care

Patients treated for colorectal cancer (CRC) experience considerable physical, social and psychological morbidity. In this study, 66 participants with stages I–III CRC were enrolled in this study. Participants completed the self‐assessment tool for patients (SATp) over a 5‐month period and visited a general practitioner with a copy of their SATp to assist in the management of any problems associated with CRC treatment. General practitioners' notes were reviewed for management actions. Of the 66 participants, 57 visited a general practitioner over the 5‐month study period. A total of 547 problems were identified (median 7; IQR: 3–12.25). Participants with physical problems were more likely to consult their general practitioner (OR: 1.84, CI: 1.05–3.21, P = 0.03) compared to those with psychological problems. The number of problems experienced by participants did not have any influence on the decision to visit a general practitioner. Psychological problems (P < 0.01) significantly reduced over the 5‐month study period. Regular use of the SATp facilitates the identification of long‐term CRC treatment‐related problems. Some of these problems could then be addressed in primary care.     

The Cambridge post-mastectomy radiotherapy (C-PMRT) index: A practical tool for patient selection

Background and purpose

Post mastectomy radiotherapy (PMRT) reduces loco-regional recurrence (LRR) and has been associated with survival benefit. It is recommended for patients with T3/T4 tumours and/or ?4 positive lymph nodes (LN). The role of PMRT in 1–3 positive LN and LN negative patients is contentious. The C-PMRT index has been designed for selecting PMRT patients, using independent prognostic factors for LRR. This study reports a 10 year experience using this index.

Materials and methods

The C-PMRT index was constructed using the following prognostic factors (a) number of positive LN/lymphovascular invasion, (b) tumour size (c) margin status and (d) tumour grade. Patients were categorised as high (H) risk, intermediate (I) risk and low (L) risk. PMRT was recommended for H and I risk patients. The LRR, distant metastasis and overall survival (OS) rates were measured from the day of mastectomy.

Results

From 1999 to 2009, 898 invasive breast cancers in 883 patients were treated by mastectomy (H: 323, I: 231 and L: 344). At a median follow up of 5.2 years, 4.7% (42/898) developed LRR. The 5-year actuarial LRR rates were 6%, 2% and 2% for the H, I and L risk groups, respectively. 1.6% (14/898) developed isolated LRR (H risk n = 4, I risk group n = 0 and L risk n = 10). The 5-year actuarial overall survival rates were 67%, 77% and 90% for H, I and L risk groups, respectively.

Conclusion

Based on published literature, one would have expected a higher LRR rate in the I risk group without adjuvant RT. We hypothesise that the I risk group LRR rates have been reduced to that of the L risk group by the addition of RT. Apart from LN status and tumour size, other prognostic factors should also be considered in selecting patients for PMRT. This pragmatic tool requires further validation.     

CHIP在乳腺癌组织中的表达及其临床意义

目的 探讨Hsc70羧基末端反应蛋白（CHIP）在乳腺癌组织中的表达及其与临床病理特征、分子分型的关系。方法 采用免疫组化检测128例乳腺癌组织中CHIP蛋白的表达,分析CHIP表达与临床病理特征以及与不同分子分型乳腺癌的关系。结果 乳腺癌组织中CHIP阳性表达率为60.2%,Ⅲ、Ⅳ期乳腺癌患者CHIP阳性表达率为43.2%,显著低于Ⅰ、Ⅱ期的67.0%;伴有淋巴结转移者CHIP阳性表达率显著低于无淋巴结转移者,差异有统计学意义（P＜0.05）; Luminal A型、Luminal B型、HER-2型、Basal-like型中CHIP阳性表达率分别为66.7%、70.5%、50.0%和44.0%,差异亦具有统计学意义（P＜0.05）。CHIP表达与年龄、组织学分级、肿瘤大小、有无远处转移及HER-2表达等无关。结论 乳腺癌CHIP表达与肿瘤发生发展密切相关,并可能作为预测患者复发风险的指标。