Introduction With the increased use of neoadjuvant therapy for breast cancer, there is a need for pre-operative prediction of prognosis. We aimed to assess the prognostic value of tumour stiffness measured by ultrasound shear wave elastography (SWE). Methods A consecutive cohort of patients with invasive breast cancer underwent breast ultrasound (US) including SWE. The following were recorded prospectively: US diameter, stiffness at SWE, presentation source, core biopsy grade, oestrogen receptor (ER) status and pre-operative nodal status. Breast cancer-specific survival (BCSS) was analysed with regard to US size and stiffness, tumour grade on core biopsy, ER status, presentation mode and pre-operative nodal status. Analysis used Cox proportional hazards regression. Results Of the 520 patients, 42 breast cancer and 53 non-breast cancer deaths were recorded at mean follow-up of 5.4 years. Hazard ratios (HR) for tertiles of stiffness were 1, 4.8 and 8.1 (P = 0.0001). HR for 2 groups based on US size < or ≥ 20 mm were 1 and 5.1 (P < 0.0001). HR for each unit increase in tumour grade on core biopsy was 3.9 (P < 0.0001). The HR for ER positivity compared to ER negativity was 0.21 (P < 0.001). BCSS was also associated with presentation mode and pre- operative nodal status. In a multivariable model, stiffness, US size and ER status were independently associated with BCSS. Conclusion Multiple pre-operative factors including stromal stiffness at SWE have independent prognostic significance. A larger dataset with longer follow-up could be used in the future to construct a pre-operative prognostic model to guide treatment decisions. Keywords Breast cancer · Prognosis · Shear wave elastography · Ultrasound · Neoadjuvant chemotherapy Introduction The assessment of prognosis has traditionally been per- * Andy Evans formed after surgical excision of breast cancer using the firstname.lastname@example.org classical prognostic factors of invasive tumour size, lymph Breast Imaging, Ninewells Hospital and Medical School, node status, histological grade and vascular invasion status Mailbox 4, Level 6, Dundee DD1 9SY, UK . These prognostic factors are then used to guide deci- Jackie Wood Cancer Centre, Ninewells Hospital and Medical sions regarding adjuvant systemic therapy. In recent years, School, Dundee DD1 9SY, UK the immunophenotype  and molecular phenotype  have Department of Breast Surgical Oncology, University of Texas also been used to inform these decisions. Online resources, MD Anderson Cancer Center, Houston, TX 77030, USA such as Predict, are also widely used to give information Pathology Department, Ninewells Hospital and Medical on overall survival and the possible benefits of adjuvant School, Dundee DD1 9SY, UK therapy. However, with the increased use of neoadjuvant Breast Surgery, Ninewells Hospital and Medical School, chemotherapy (NACT) there is a need for accurate pre- Dundee DD1 9SY, UK operative prediction of prognosis to aid treatment selection. Department of Public Health and Primary Care, Department Pre-operatively, tumour size can be estimated from imaging of Oncology, Strangeways Research Laboratory, Worts and histological grade and ER and HER-2 status determined Causeway, Cambridge CB1 8RN, UK Vol.:(0123456789) 1 3 384 Breast Cancer Research and Treatment (2018) 171:383–389 from the core biopsy . Mode of presentation (through and breast cancer survival in a consecutive cohort of women mammographic screening or symptoms) has also been diagnosed with ultrasound visible, invasive breast cancer. shown to affect outcome even when adjusted for pathological variables such as invasive tumour size and nodal status . Ultrasound of the axilla with biopsy of abnormal nodes is Methods diagnostic for approximately 50% of node-positive patients . However, given the debate regarding the need for clear- SWE, US, source of referral and histopathological details ance of all positive axillae, vigorous efforts to diagnose (including core biopsy grade, ER, HER-2 status and pre- every positive axilla pre-operatively are being discouraged operative nodal status) were collected prospectively from a by some surgeons . There is, therefore, a need for more consecutive series of patients undergoing diagnostic breast reliable tools for the pre-operative assessment of prognosis. examination for lesions subsequently shown to be invasive The tumour microenvironment greatly contributes to can- breast cancer (n = 540). Between April 2010 and January cer growth, dissemination and drug resistance. One of the 2013, all women had their US lesion diameter and mean key features involved in these functions is the extracellular stiffness (kPa) at SWE recorded irrespective of subsequent matrix (ECM) remodelling. This process is characterised by treatment (primary surgery, neoadjuvant systemic therapy an increased number of stromal cells, an increased secretion and primary endocrine therapy). The core biopsy grade was of extracellular matrix proteins as well as thickening and recorded to allow inclusion of this parameter in assessment reorganization of the collagen fibrils which results in stiffen- of prognosis pre-operatively. ER status and HER-2 status ing of the stroma . A biophysical and histological study are routinely measured in our institution on the core biopsy has shown that stromal stiffness is higher at the invasive rather than the surgical resection specimen in line with cur- front of the most aggressive breast tumours (HER2 ampli- rent guidelines. All women had axillary US and core biopsy fied and triple-negative breast cancer, TNBC) compared to of abnormal nodes (cortex > 2.3 mm) for assessment of the less aggressive luminal tumours, suggesting an associa- nodal status. tion between stiff stroma and cancer aggression [9 ]. Conklin All US scans were performed by one of five breast radi- et al. have correlated collagen fibril orientation with poor ologists or an advanced radiography practitioner trained to survival regardless of tumour grade, size, node status and perform and interpret breast ultrasound. These practitioners tumour subtype in breast cancer . In vitro studies have had between 7 and 22 years of breast ultrasound experience demonstrated that substrate stiffness mediates drug resist- and had at least 12 months of experience performing SWE ance in breast cancer cell lines . In the neoadjuvant set- of solid breast lesions. Four SWE images in two orthogonal ting, a stromal gene signature enriched in ECM protein was planes were obtained. The region of interest (ROI) utilized found to be associated with poor response to 5-fluorouracil, in all cases was 2 mm in diameter. Mean stiffness in kPa epirubicin and cyclophosphamide treatment . All these was taken as the average of the values taken from four SWE findings led us to investigate stromal stiffness measured by images taken in two orthogonal planes. The maximum US shear wave elastography (SWE) as a prognostic marker of diameter used in the analysis was the largest obtained in breast cancer survival. Shear wave elastography (SWE) is an any of the three planes. All scans were performed using an ultrasound imaging method which allows quantification of Aixplorer® ultrasound system (SuperSonic Imagine, Aix lesional and peri-lesional stiffness and it has been shown to en Provence, France). Institutional Review Board ethical aid benign/malignant differentiation of breast masses . approval was waived for this retrospective analysis of pro- SWE is highly reproducible and quantitative . Both stiff- spectively recorded data and all patients gave permission for ness at SWE and strain elastography have been shown to evaluation of their images. be predictors of nodal metastasis, independent of invasive Patient’s survival including cause of death was ascer- tumour size, histological grade and vascular invasion status tained from local paper and electronic health records and [15, 16]. Stiffness at SWE has a strong relationship with the National Cancer Registry. Patients that died after devel- invasive tumour size, histological grade and poor outcome oping metastatic breast cancer were assumed to have died immunophenotypes [17, 18]. Stiffness at elastography has of breast cancer. A total of 20 patients were excluded from also been shown, in some studies, to be associated with the analysis on the following grounds: Twelve patients with chemotherapy resistance [19–21]. metastases at presentation; five where cause of death could We therefore postulated that stiffness at SWE may be not be ascertained; two with no follow-up data; and one with related to the prognosis of women with breast cancer. No a history of a previous breast cancer. previous studies have addressed this question. The aim of BCSS was assessed using Kaplan–Meier survival the study is to investigate associations between prospectively curves. Association between putative prognostic vari- collected pre-operative factors (including stromal stiffness) ables and BCSS was evaluated using Cox proportional hazards regression. Variables included in Cox models 1 3 Breast Cancer Research and Treatment (2018) 171:383–389 385 were mean stiffness, tumour size, tumour grade, ER sta- Results tus, presentation source (screening or symptomatic) and pre-operative nodal status. Mean stiffness was categorized After the 20 exclusions detailed above, 520 patients con- into three equal size groups and size into two groups (< 20 stituted the study group (mean age 62 years, median age or ≥ 20 mm). 62 years and range 28–95 years). Two hundred and five (39%) patients had their cancer diagnosed at mammographic screening while 315 (61%) women had symptomatic can- cers. The pathological characteristics of the tumours are shown in Table 1. Four hundred and twenty-one women underwent immediate surgery and surgical nodal staging of Table 1 Pathological and immunohistochemical characteristics of whom 42% had invasive cancers ≥ 20 mm in size and 29% study cancers had axillary macro-metastases. Of the remaining 99, four Histological grade 1 60 (12%) women had immediate surgery but did not undergo nodal Histological grade 2 225 (43%) staging. Forty-five women were treated with NACT and 11 Histological grade 3 235 (45%) had neoadjuvant endocrine therapy. Thirty-nine women were Ductal carcinoma of no specific type 399 (77%) treated using primary endocrine therapy due to severe co- Lobular cancer 65 (13%) morbidities. The mean follow-up in women still alive at the Tubular cancer 19 (4%) time of reporting was 5.4 years. < 10 mm 57 (13%) Forty-two women of the 520 died of breast cancer (8%) 10–20 mm 189 (44%) while 53 women had non-breast cancer deaths (10%) during 21–30 mm 103 (24%) the follow-up period. Kaplan–Meier survival curves for three > 30 mm 76 (18%) equal size groups based on stiffness are shown in Fig. 1 and Vascular invasion 108 (25%) curves by US size in Fig. 2. Kaplan–Meier survival curves Node positive (macro-metastases) 122 (29%) according to core biopsy grade are shown in Fig. 3. ER positive 429 (83%) All variables except HER-2 were significantly associated PR positive 373 (72%) with BCSS in univariable Cox regression models (Table 2). HER-2 positive 63 (12%) However, in a multivariable model, grade and mode of detec- tion were no longer significant at a nominal P < 0.1 and these As not all patients had immediate surgery denominators for vascular invasion, nodal status and invasive size vary Fig. 1 Kaplan-Meier survival bcss curves for three equal size groups based on stiffness at shear wave elastography 90 stiffness_group 012 3 456 78 Time Number at risk Group: 1 176171 166158 14681171 0 Group: 2 174168 164157 14884270 0 Group: 3 170163 155141 12470281 0 1 3 Survival probability (%) 386 Breast Cancer Research and Treatment (2018) 171:383–389 Fig. 2 Kaplan-Meier survival curves according to ultrasound size Fig. 3 Kaplan-Meier survival bcss curves according to core biopsy estimated histological grade core_grade 01 23 45 67 8 Time Number at risk Group: 1 61 60 59 58 53 28 60 0 Group: 2 259248 243232 211117 34 10 Group: 3 200194 183166 15490321 0 variables were excluded from the final multivariable model BCSS (tertile 2 vs tertile 1 HR = 3.4, 95% CI 0.95–12 and (Table 2). In this model, stiffness was strongly associated with tertile 3 vs tertile 1 HR = 4.7, 95% CI 1.4–16). 1 3 Survival probability (%) Breast Cancer Research and Treatment (2018) 171:383–389 387 Table 2 Results of univariable and multivariable analyses of pre-operative prognostic markers Univariable model Multivariable model Final multivariable model HR 95% CI P value HR 95% CI P value HR 95% CI P value Stiffness Tertile 2 vs 1 4.9 1.4–17 0.013 2.7 0.76–9.8 0.12 3.4 0.95–12 0.06 Tertile 3 vs 1 8.2 2.5–27 0.0006 4 1.2–14 0.028 4.7 1.4–16 0.013 Size − 7 20+ mm vs < 20 mm 5.4 2.8–11 8 × 10 2.8 1.4–5.7 0.0023 3.5 1.8–7.0 0.00033 − 5 Core grade 3.9 2.1–7.2 2 × 10 1.8 0.83–3.8 0.14 Pre-op node positive 2.9 1.5–5.6 0.0014 1.8 0.90–3.6 0.096 2 1.0–3.9 0.047 − 7 − 6 ER positive 0.21 0.11–0.38 4 × 10 0.31 0.15–0.63 0.0014 0.23 0.13–0.43 3 × 10 Screen vs clinical detection 5.1 2.0–13 0.00065 1.7 0.64–4.7 0.28 HER-2 1.3 0.55.–3.11 0.55 0.63 0.26–1.5 0.31 higher contractibility capacities and maintenance of ECM Discussion protein secretion that further contributes to tissue stiffen- ing. Indeed, CAFs have been shown in vitro to cause an We have shown that US size, SWE stiffness, ER status and eightfold increase in matrix stiffness compared with nor - pre-operative nodal status are independent pre-operative mal fibroblasts through the production of thicker collagen predictors of prognosis in invasive breast cancer. The other and increased collagen cross linking by lysyl oxidase [27, pre-operative factors studied (core grade, and presentation) 28]. This process results in the release of active TGFb failed to reach statistical significance at multivariate analy - which also maintains CAFs into their active form . sis but given the small number of events (n = 42) this could As well as being a risk factor for breast cancer develop- reflect the limited power of the study rather than true lack ment, stiffening of the tumour stroma has been shown to of effect. enhance several key functions of tumour development. It If these factors are shown to be prognostic in larger and does so by triggering mechano-responses of the tumour independent datasets, then a pre-operative prognostic model cells through mechano-sensors such as integrins . could be constructed and validated in the future. Such a pre- More particularly, in vivo and in vitro breast models have operative prognostic model could also be used to guide clini- shown that activation of the focal adhesion kinase (FAK), cal decisions such as the appropriateness of NACT. Current in response to stiff tissue, promotes tumour cell prolifera- prognostic models such as the NPI  and PREDICT use tion and an invasive phenotype . Moreover, perpen- post-operative factors so cannot be used pre-operatively. dicular orientation of the collagen bundles to the primary Grey scale US is used globally to evaluate breast masses, lesion observed in stiff tissue allows tumour cells migra- while SWE has gained use in recent years, and is now avail- tion towards blood vessels as well as myeloid cell infiltra- able from many leading equipment manufacturers. Perform- tion . Tumour cell dissemination is also encouraged by ing SWE takes about 2 min per patient and reading the stiff- the increased vascularisation which develops in response ness from the acquired images also takes 2 min per patient to stiffness-associated hypoxia. Stiff ECM also induces . In this study, we used E measurements but E mean max drug resistance by limiting therapeutic agent diffusion and measurement give equally good results in studies of benign/ by activating cellular pathways involved in tumour cell malignant differentiation . Including SWE in the routine survival . imaging examination of solid breast masses would there- This non-exhaustive list of the pro-tumoural effects of fore not be difficult to introduce in most breast clinics. Core stiff stroma surrounding breast tumour cells provides clues biopsy ER status is also routinely available in nearly every as to why stiff tissue measurement by shear wave elastogra- case of both screening and symptomatic invasive cancer. phy is a prognostic marker of breast cancer patient survival. The stiffness within breast cancers at SWE is predomi- Breast MRI, particularly diffusion-weighted imaging has nantly seen at the tumour/stromal boundary and in the been shown to correlate both with prognostic factors such peri-tumoural stroma [9, 16, 23]. This stiffness appears to as tumour size, histological grade and nodal positivity [32, be due to the nature of the collagen produced by tumour- 33] and in combination with other imaging parameters may associated stromal cells (fibroblasts and cancer-associated improve pre-operative prognostication. fibroblasts (CAFs)) . An increase in stromal stiff- Core biopsy ER status is routinely used to guide deci- ness induces activation of the CAFs into myofibroblasts sions regarding pre-operative therapy and is preferred by expressing aSMA  and SNAIL1  resulting in 1 3 388 Breast Cancer Research and Treatment (2018) 171:383–389 Open Access This article is distributed under the terms of the Crea- many to ER status derived from the surgical specimen due tive Commons Attribution 4.0 International License (http://creat iveco better fixation of the small sample. mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- The four factors found to be independently significant tion, and reproduction in any medium, provided you give appropriate are therefore based on the biology of the tumour (ER credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. status), the tumour microenvironment (stiffness) and the time-dependent variables of lesion size (as measured by ultrasound) and pre-operative nodal status. 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