The 70-gene signature (MammaPrint) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment. Given the strong association between locoregional and distant recurrence, we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence (LRR). 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherlands Cancer Institute between 1984 and 2006 were included. Adjuvant treatment consisted of radiotherapy, chemotherapy, and/or endocrine therapy as indicated by guidelines used at the time. All patients were included in various 70-gene signature validation studies. After a median follow-up of 8.96 years with 87 LRRs, patients with a high-risk 70-gene signature (n = 492) had an LRR risk of 12.6% (95% CI 9.7-15.8) at 10 years, compared to 6.1% (95% CI 4.1-8.5) for low-risk patients (n = 561; P < 0.001). Adjusting the 70-gene signature in a competing risk model for the clinicopathological factors such as age, tumour size, grade, hormone receptor status, LVI, axillary lymph node involvement, surgical treatment, endocrine treatment, and chemotherapy resulted in a multivariable HR of 1.73 (95% CI 1.02-2.93; P = 0.042). Adding the signature to the model based on clinicopathological factors improved the discrimination, albeit non-significantly [C-index through 10 years changed from 0.731 (95% CI 0.682-0.782) to 0.741 (95% CI 0.693-0.790)]. Calibration of the prognostic models was excellent. The 70-gene signature is an independent prognostic factor for LRR. A significantly lower local recurrence risk was seen in patients with a low-risk 70-gene signature compared to those with high-risk 70-gene signature.
Optimal local control is one of the three main aims of breast cancer treatment (next to optimal regional control and reducing the risk of distant relapses by adequate systemic treatments). To this end, many women desire breast conservation provided local control is comparable to that of ablative procedures, the cosmetic outcome is good and side effects of treatment are limited. To achieve this delicate balance the following should be part of the information to the patient with an operable breast cancer: Patients should have an open discussion with there care providers to enable a shared decision: this will lead to less anxiety and stress with the best satisfaction and recovery. The possibility of breast conservation should always be explored. Even with equal local control and survival outlook, quite a minority (about 20%) of patients opt for ablative procedures (with or without breast reconstruction). Higher risk of local relapse (i.e. persistent cancer growth in the breast) is associated with higher risk of distant disease and subsequent risk of dying of breast cancer. Rough estimates indicate that for every four local relapses one patient may die from breast cancer due to persistent disease. This estimate may vary substantially with the type of cancers (see dr. Morrow), age at diagnosis, application and duration of systemic treatments. To limit the negative effect on overall survival through local relapses, it is generally accepted that for early breast cancer local relapse rates should be within the limit of 1% per year, or within 10% at 10 years. Current population based overviews and hospital based studies show that the risk of local relapse after breast conservations are very well below this limit, being around 2-3% at 5 years. There is no absolute risk threshold of local relapse incidence above which breast conservation is absolutely contra indicated: this will remain an individual decision. Oncoplastic procedures should widely be available to adjust to the width of the local excision and to improve cosmetic outcome. In larger cancers, the option of neo-adjuvant chemotherapy must be considered: about one-third of "mastectomy candidates" can be conversed to an oncologically safe breast conservation. The most important independent risk factors for a breast relapse are: more than focally incomplete margins (roughly 2 times increased risk), young age (<35 years, 2 times increased risk) no radiotherapy (2-4 times increased risk). These risk factors again may also be influenced by the biological type of breast cancer. Combination of risk factors should be added: e.g. young women (<35 years) who had breast conservation for DCIS without radiotherapy may face 15 years breast relapse rate of over 40%. In aggregate, in the following clinical situations the increased risk of breast relapse should be extensively discussed with the patient and breast conservation should be executed with caution: Very young women (<35 years) Extensive DCIS (heralded by extensive microcalcifications) mounting up to one quarter of the brea...
Multifocal (MF) and multicentric (MC) breast cancer is regularly considered a relative contraindication for breast-conserving therapy (BCT). There are two reasons for this wide spread notion: However, we concur that if optimal 'cytoreductive surgery' is achieved this will result in good local control (i.e. in-breast relapse <10% at 10 years). This can only be achieved on the basis of the right imaging, image guidance for non-palpable foci, and tumor free (invasive as well as ductal carcinoma in situ) margins after adequate pathological assessment. Surgery must then be followed by whole breast irradiation and systemic treatments as indicated by primary cancer biology. Careful planning and adaptive application of oncoplastic techniques will result in an optimal cosmetic results. The meticulous work of Roland Holland and coworkers(1) in the early 1980's on whole breast specimen showed invasive foci at more then 2 cm distance from the invasive primary cancer in more then 40% of specimen. Although multiple tumor foci may occur in up to 60% of mastectomy specimens, equivalent survival outcomes were observed in prospective trials comparing BCT and mastectomy for clinically unifocal lesions, suggesting that the majority of these foci are not, or do not become, biologically relevant or clinically significant with appropriate treatment. As diagnostic tools advance, MF and MC tumors are more commonly diagnosed. Cancers that previously would have been classified as unifocal now can be detected as MF or MC. In addition, locoregional treatment modalities have improved significantly over the past decade. More recent studies reflect these advances in diagnosis and treatment. Studies evaluated staging MRI showed that up to 19% of woman with diagnosed breast cancer harbor a second malignant ipsilateral lesion. These findings should only have consequences when additional lesions are proven cancer. Multiple enhancing lesions on MRI are in itself not an indication for a mastectomy. The Z0011 trial and the AMAROS trial demonstrated a similar phenomenon for axillary treatment; less surgery does not necessarily lead to inferior local control or survival outcomes. Recent studies supplement the growing evidence that treatment of patients with MF/MC breast cancer with BCS, radiotherapy, and adjuvant systemic therapy can result in low rates of in-breast recurrence.
Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-2954-2) contains supplementary material, which is available to authorized users.
: This study shows that the tissue retrieval sequence in multitissue donors is the most important factor associated with the occurrence of bleeding complications. The risk of bleeding and ocular hematoma is lower if cornea donation is performed after all other retrievals. However, if the tissue retrieval sequence is altered, the effect of prolonged postmortem time on corneal quality must be taken into account.
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