Economic Impact of Gene Expression Profiling in Patients with Early-Stage Breast Cancer in France

Background and Aims

The heterogeneous nature of breast cancer can make decisions on adjuvant chemotherapy following surgical resection challenging. Oncotype DX is a validated gene expression profiling test that predicts the likelihood of adjuvant chemotherapy benefit in early-stage breast cancer. The aim of this study is to determine the costs of chemotherapy in private hospitals in France, and evaluate the cost-effectiveness of Oncotype DX from national insurance and societal perspectives.

Methods

A multicenter study was conducted in seven French private hospitals, capturing retrospective data from 106 patient files. Cost estimates were used in conjunction with a published Markov model to assess the cost-effectiveness of using Oncotype DX to inform chemotherapy decision making versus standard care. Sensitivity analyses were performed.

Results

The cost of adjuvant chemotherapy in private hospitals was estimated at EUR 8,218 per patient from a national insurance perspective and EUR 10,305 from a societal perspective. Cost-effectiveness analysis indicated that introducing Oncotype DX improved life expectancy (+0.18 years) and quality-adjusted life expectancy (+0.17 QALYs) versus standard care. Oncotype DX was found cost-effective from a national insurance perspective (EUR 2,134 per QALY gained) and cost saving from a societal perspective versus standard care. Inclusion of lost productivity costs in the modeling analysis meant that costs for eligible patients undergoing Oncotype DX testing were on average EUR 602 lower than costs for those receiving standard care.

Conclusions

As Oncotype DX was found both cost and life-saving from a societal perspective, the test was considered to be dominant to standard care. However, the delay in coverage has the potential to erode the quality of the French healthcare system, thus depriving patients of technologies that could improve clinical outcomes and allow healthcare professionals to better allocate hospital resources to improve the standard of care for all patients.     

A Clinicopathological Study of Early-Stage Synchronous Bilateral Breast Cancer: A Retrospective Evaluation and Prospective Validation of Potential Risk Factors

Background

The aim of the present study was to investigate potential risk factors for synchronous bilateral breast cancer sBBC).

Methods

A retrospective analysis was performed of patients diagnosed and treated with operable bilateral breast cancer (BBC) between June 2007 and December 2011. Risk factors for sBBC were evaluated in this cohort and further validated in a prospective observational validation analysis of patients between January 2012 and December 2012. Patients treated with operable unilateral breast cancer during the same period were used as a control group.

Results

A total of 11,247 patients with primary breast cancer underwent operations at the Fudan University Shanghai Cancer Center between June 2007 and December 2012. The incidence of sBBC was 1.6%. The age at diagnosis (HR = 2.4, 95% C.I.: 1.4–4.0, p = 0.001), presence of sclerosing adenosis (HR = 11.8, 95% C.I.: 5.3–26.3, p<0.001), lobular carcinoma component involvement (HR = 5.6, 95% C.I.: 2.6–12.1, p<0.001), and family history of first-degree relatives with breast cancer (HR = 2.0, 95% C.I.: 1.1–3.4, p<0.001) were independent risk factors for sBBC. A subsequent validation study failed to confirm the significance of family history. No significant difference on survival was found between patients with early-stage sBBC and control cases.

Conclusions

Patients with the presence of sclerosing in the affected breast, and lobular carcinoma component involvement may be at high risk for developing sBBC. This study supports the hypothesis that the host-carcinoma biological relationship, especially for the tumor microenvironment, played a critical role in the carcinogenesis of sBBC.     

Alterations in Circulating miRNA Levels following Early-Stage Estrogen Receptor-Positive Breast Cancer Resection in Post-Menopausal Women

Introduction

Circulating microRNAs (miRNAs) exhibit remarkable stability and may serve as biomarkers in several clinical cancer settings. The aim of this study was to investigate changes in the levels of specific circulating miRNA following breast cancer surgery and evaluate whether these alterations were also observed in an independent data set.

Methods

Global miRNA analysis was performed on prospectively collected serum samples from 24 post-menopausal women with estrogen receptor-positive early-stage breast cancer before surgery and 3 weeks after tumor resection using global LNA-based quantitative real-time PCR (qPCR).

Results

Numbers of specific miRNAs detected in the samples ranged from 142 to 161, with 107 miRNAs detectable in all samples. After correction for multiple comparisons, 3 circulating miRNAs (miR-338-3p, miR-223 and miR-148a) exhibited significantly lower, and 1 miRNA (miR-107) higher levels in post-operative vs. pre-operative samples (p<0.05). No miRNAs were consistently undetectable in the post-operative samples compared to the pre-operative samples. Subsequently, our findings were compared to a dataset from a comparable patient population analyzed using similar study design and the same qPCR profiling platform, resulting in limited agreement.

Conclusions

A panel of 4 circulating miRNAs exhibited significantly altered levels following radical resection of primary ER+ breast cancers in post-menopausal women. These specific miRNAs may be involved in tumorigenesis and could potentially be used to monitor whether all cancer cells have been removed at surgery and/or, subsequently, whether the patients develop recurrence.     

Prolactin Concentrations in Patients with Breast Cancer

Basal prolactin levels were measured before operation in 113 patients undergoing surgery for a lump in the breast. Prolactin concentrations were not significantly higher in those patients with breast cancer than in those with benign lumps. Prolactin concentrations were, however, found to be higher in premenopausal women than in postmenopausal ones, regardless of tumour histology.     

Management of Breast Cancer in Old Age

In a retrospective survey of 301 women aged over 70 with breast cancer the factors affectingfive-year survival are evaluated. The local disease is more advanced when the patient presents with it in old age than in younger women, possibly associated with a lesser degree of awareness or a long history of the primary tumour. It is not associated with a different average rate of tumour growth in old age, as measured by scar recurrences after surgery. Radical surgery may be followed by a high five-year survival rate in patients carefully selected on medical grounds, but in this unselected series the five-year survival rate was practically the same whether the local disease was limited or extensive at presentation and whatever the treatment given. The probability of five-year survival in a woman over 70 with breast cancer will depend mainly on her general health.     

乳腺癌免疫组化检测在乳腺癌患者诊治中的意义分析

目的：探讨免疫组化检测在乳腺癌患者诊治中的价值。方法：随机选取2011年1月-2013年1月的68例经过空心穿刺活捡并病理确诊的乳腺癌患者为研究对象,均采用免疫组化检测ER、PR、P53、Bcl-2,全部采用CEF化疗方案治疗3个月后手术治疗,再运用免疫组化SP法检测化疗前后乳腺癌组织中以上指标的阳性表达率情况。结果：ER、PR化疗前后比较无统计学意义（P〉0．05）;而P53、Bcl-2比较有明显的差异性（P〈0．05）;ER、PR的阴性和阳性和疗效情况无明显差异性,而P53、Bcl-2的阴性和阳性表达和化疗的效果有明显的差异性,P〈0．05,具有统计学意义。结论：免疫组化检测中ER、PR对乳腺癌化疗前后无明显差异性,而化疗可通过抑制P53的表达来抑制乳腺癌增值并通过升高Bcl-2表达来调整肿瘤细胞分化。     

Carcinoembryonic Antigen in Patients With Breast or Colon Cancer

The rationale and results of clinical use of carcinoembryonic antigen (CEA) tests in patients with carcinoma of the breast and colon deserve review. Plasma CEA levels have been found to correlate with the extent of tumor invasion and site of metastatic spread, and CEA titers have diagnostic and prognostic value. Although postresectional serial CEA testing is not as useful in cases of breast carcinoma, in cases of carcinoma of the colon it may indicate recurrence or progression of the lesion. However, there are limitations and CEA results should be interpreted in conjunction with other clinical information.     

Progress of Breast Cancer basic research in China

Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.     

Analysis of Gut Microbiota in Patients with Breast Cancer and Benign Breast Lesions

Breast cancer (BC) and benign breast lesions (BBLs) are common diseases in women worldwide. The gut microbiota plays a vital role in regulating breast diseases’ formation, progression, and therapy response. Hence, we explored the structure and function of gut microflora in patients with BC and BBLs. A cohort of 66 subjects was enrolled in the study. Twenty-six subjects had BC, 20 subjects had BBLs, and 20 matched healthy controls. High throughput 16S ribosomal RNA (16S rRNA) gene sequencing technology was used to determine the microbial community structure. Compared with healthy individuals, BC patients had significantly lower alpha diversity indices (Sobs index, p = 0.019; Chao1 index, p = 0.033). Sobs and Chao1 indices were also lower in patients with BBLs than healthy individuals, without statistical significance (p = 0.279, p = 0.314, respectively). Both unweighted and weighted UniFrac analysis showed that beta diversity differed significantly among the three groups (p = 3.376e–14, p < 0.001, respectively). Compared with healthy individuals, the levels of Porphyromonas and Peptoniphilus were higher in BC patients (p = 0.004, p = 0.007, respectively), whereas Escherichia and Lactobacillus were more enriched in the benign breast lesion group (p < 0.001, p = 0.011, respectively). Our study indicates that patients with BC and BBLs may undergo significant changes in intestinal microbiota. These findings can help elucidate the role of intestinal flora in BC and BBLs patients. Open in a separate window     

Effect of Neoadjuvant Chemotherapy on the Serum Levels of Bone Turnover Markers in Women with Early-Stage Breast Cancer

Background

To evaluate effects of neoadjuvant chemotherapy on the bone turnover markers of preoperational breast cancer patients.

Methods

Forty-one breast cancer patients (29 premenopausal and 12 postmenopausal) and 60 healthy women (30 premenopausal and 30 postmenopausal) aged 30-64 years, were evaluated for their bone status. Serum levels of the bone formation markers PINP and BAP, as well as the resorption markers ICTP and β-Crosslaps in addition to E2, FSH, 25(OH)D and PTH were measured at the initial diagnosis and at 24 hours after each four chemotherapy cycles. BMD T-scores were determined in 12 patients 6 months after the neoadjuvant chemotherapies.

Results

The baseline levels of both bone formation and resorption markers in premenopausal patients were higher than in premenopausal healthy women (p<0.05), while no statistic difference was observed between postmenopausal patients and postmenopausal healthy women. Regardless of the menopausal status, chemotherapy increased the ICTP and β-Crosslaps levels (p<0.05), but decreased the BAP and PINP levels (p<0.05), the later one significantly more with Taxane medication (p<0.01, p<0.05). Chemotherapy caused significant decreases of 25(OH)D levels in premenopausal (p<0.01) and postmenopausal (p<0.05) patients, however, did not affect the PTH concentrations. In premenopausal patients the E2 level decreased, while the FSH level increased after chemotherapy (p<0.05). Patients with pronounced ICTP and β-Crosslaps combined with reduced BAP and PINP serum concentrations after neoadjuvant chemotherapies were prone to develop osteoporosis 6 month later.

Conclusions

Neoadjuvant chemotherapy appeared to promote bone resorption and inhibit bone formation in both postmenopausal and premenopausal early-stage breast patients.     

术前空芯针穿刺与开放性手术活检对乳腺癌患者临床预后的影响

目的:探讨术前空芯针穿刺与开放性手术活检对乳腺癌患者临床预后的影响,为乳腺癌相关临床研究提供参考。方法:选取2010年12月至2014年12月我院临床收治的早期乳腺癌患者380例为研究对象,根据诊断方法不同将患者分为术前针穿刺组(n=92)和手术活检组(n=288),观察并比较两组患者的相关临床指标及无病生存率水平进行观察和比较。结果:两组患者的年龄、淋巴结转移发生率、肿瘤分级情况、ER阳性表达率、PR阳性表达率和HER-2阳性表达率水平差异不大,且组间比较无统计学意义(P0.05);研究组患者的肿瘤直径≥2 cm患者的比例显著高于对照组,且差异有统计学意义(P0.01);研究组和对照组术后24个月的无病生存率分别为98.91%和99.65%,组间比较差异无统计学意(P0.05);研究组和对照组术后36个月的无病生存率分别为95.65%和96.18%,组间比较差异无统计学意义(P0.05)。结论:早期乳腺癌患者术前采用空芯针穿刺活检对于患者的预后没有显著影响,可以作为临床诊断患者病情的有效方法之一。     

Abnormal Excretion of Corticosteroid Sulphates in Patients with Breast Cancer

In a preliminary study, the 24-hour urinary excretion of corticosteroid sulphates and free cortisol have been measured in a group of patients with breast cancer and compared with the excretion of the same compounds in a group of normal women of similar age. Excretion of corticosteroid sulphates in the breast cancer group was found to be markedly raised. In a small number of patients with localized cancer of sites other than the breast the level of corticosteroid sulphate was not raised. If proved metastases were present a noticeable rise was observed.     

Use of Formalin-Fixed Paraffin-Embedded Samples for Gene Expression Studies in Breast Cancer Patients

To obtain gene expression profiles from samples collected in clinical trials, we conducted a pilot study to assess feasibility and estimate sample attrition rates when profiling formalin-fixed, paraffin-embedded specimens. Ten matched fresh-frozen and fixed breast cancer samples were profiled using the Illumina HT-12 and Ref-8 chips, respectively. The profiles obtained with Ref 8, were neither technically nor biologically reliable since they failed to yield the expected separation between estrogen receptor positive and negative samples. With the use of Affymetrix HG-U133 2.0 Plus chips on fixed samples and a quantitative polymerase chain reaction -based sample pre-assessment step, results were satisfactory in terms of biological reliability, despite the low number of present calls (M = 21%±5). Compared with the Illumina DASL WG platform, Affymetrix data showed a wider interquartile range (1.32 vs 0.57, P<2.2 E-16,) and larger fold changes. The Affymetrix chips were used to run a pilot study on 60 fixed breast cancers. By including in the workflow the sample pre-assessment steps, 96% of the samples predicted to give good results (44/46), were in fact rated as satisfactory from the point of view of technical and biological meaningfulness. Our gene expression profiles showed strong agreement with immunohistochemistry data, were able to reproduce breast cancer molecular subtypes, and allowed the validation of an estrogen receptor status classifier derived in frozen samples. The approach is therefore suitable to profile formalin-fixed paraffin-embedded samples collected in clinical trials, provided that quality controls are run both before (sample pre-assessment) and after hybridization on the array.     

Bone Health History in Breast Cancer Patients on Aromatase Inhibitors

A cross-sectional study was performed to assess bone health history among aromatase inhibitor (AI) users before breast cancer (BC) diagnosis, which may impact fracture risk after AI therapy and choice of initial hormonal therapy. A total of 2,157 invasive BC patients initially treated with an AI were identified from a prospective cohort study at Kaiser Permanente Northern California (KPNC). Data on demographic and lifestyle factors were obtained from in-person interviews, and bone health history and clinical data from KPNC clinical databases. The prevalence of osteoporosis and fractures in postmenopausal AI users was assessed, compared with 325 postmenopausal TAM users. The associations of bone health history with demographic and lifestyle factors in AI users were also examined. Among all initial AI users, 11.2% had a prior history of osteoporosis, 16.3% had a prior history of any fracture, and 4.6% had a prior history of major fracture. Postmenopausal women who were taking TAM as their initial hormonal therapy had significantly higher prevalence of prior osteoporosis than postmenopausal AI users (21.5% vs. 11.8%, p<0.0001). Among initial AI users, the associations of history of osteoporosis and fracture in BC patients with demographic and lifestyle factors were, in general, consistent with those known in healthy older women. This study is one of the first to characterize AI users and risk factors for bone morbidity before BC diagnosis. In the future, this study will examine lifestyle, molecular, and genetic risk factors for AI-induced fractures.