Obesity-associated changes in molecular biology of primary breast cancer.

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

The frequency and clinical significance of centromere enumeration probe 17 alterations in human epidermal growth factor receptor 2 immunohistochemistry-equivocal invasive breast cancer.

BACKGROUND AND AIMS: Chromosome 17 alterations affect the assessment of HER2 gene amplification in breast cancer (BC), but its clinical significance remains unclear. This study aimed to identify the prevalence of centromere enumeration probe 17 (CEP17) alterations, and its correlation with response to neoadjuvant therapy (NAT) in BC patients with human epidermal growth factor receptor 2 (HER2) immunohistochemistry-equivocal score. METHODS AND RESULTS: A large BC cohort (n = 6049) with HER2 immunohistochemistry score 2+ and florescent in-situ hybridisation (FISH) results was included to assess the prevalence of CEP17 alterations. Another cohort (n = 885) with available clinicopathological data was used to evaluate the effect of CEP17 in the setting of NAT. HER2-amplified tumours with monosomy 17 (CEP17 copy number < 1.5 per nucleus), normal 17 (CEP17 1.5-< 3.0) and polysomy 17 (CEP17 ≥ 3.0) were observed in 16, 59 and 25%, respectively, compared with 3, 74 and 23%, respectively, in HER2-non-amplified tumours. There was no significant relationship between CEP17 alterations and pathological complete response (pCR) rate in both HER2-amplified and HER2-non-amplified tumours. The independent predictors of pCR were oestrogen (ER) negativity in HER2-amplified tumours [ER negative versus positive; odds ratio (OR) = 11.80; 95% confidence interval (CI) = 1.37-102.00; P = 0.02], and histological grade 3 in HER2 non-amplified tumours (3 versus 1, 2; OR = 5.54; 95% CI = 1.61-19.00; P = 0.007). CONCLUSION: The impacts of CEP17 alterations are not as strong as those of HER2/CEP17 ratio and HER2 copy number. The hormonal receptors status and tumour histological grade are more useful to identify BC patients with a HER2 immunohistochemistry-equivocal score who would benefit from NAT.

Post-intensive care syndrome following cardiothoracic critical care: Feasibility of a complex intervention.

OBJECTIVES: To describe the long-term outcomes of cardiac intensive care unit patients and their primary caregivers, and to explore the feasibility of implementing a complex intervention, designed to support problems associated with post-intensive care syndrome and post-intensive care syndrome-family, in the year following discharge from the cardiac intensive care unit. DESIGN: A complex multidisciplinary rehabilitation programme, delivered as a quality improvement initiative, in a single centre in the West of Scotland. Outcomes were measured using surveys of health related quality of life, self efficacy, anxiety, depression, pain, caregiver strain, and insomnia. PARTICIPANTS: Patients and their caregivers were invited to participate 12 weeks after hospital discharge. Twenty-seven patients and 23 caregivers attended the programme. RESULTS: Over 90% of patients had problems in at least one quality of life domain at baseline, 41% of patients had symptoms of anxiety and 22% had symptoms of depression. During the baseline visit, caregiver strain was present in 20% of caregivers, 57% had symptoms of anxiety, and 35% had symptoms of depression. Improvements in outcomes were seen in both patients and caregivers at 1-year follow-up. The programme was implemented, and iterative learning obtained about the content and the operationalization of the service, in order to understand feasibility. CONCLUSION: This small-scale quality improvement project has demonstrated that this complex multidisciplinary rehabilitation programme is feasible and has positive implications for patients following discharge from the cardiac intensive care unit, and their caregivers.

Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases.

BACKGROUND: The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT). METHODS: 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. RESULTS: 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017). CONCLUSION: No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.

Predictors of pathological complete response to neoadjuvant treatment and changes to post-neoadjuvant HER2 status in HER2-positive invasive breast cancer.

The response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2 amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2 amplified tumours, when either in receipt of NACT alone (38% versus 13%; p = 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p < 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2 amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2 amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.

The prognostic impact of mode of detection of axillary metastases for women with invasive breast cancer: A retrospective observational study.

AIM: To identify the breast cancer specific survival (BCSS) associated with nodal metastasis identified by axillary core biopsy (ACB), and by sentinel node biopsy (SNB) compared with node negative patients. A further aim was to assess the prognostic effects of axillary ultrasound (US) features and amount of tumour in ACB specimens. METHODS: Consecutive patients with cancer were identified from a database of US lesions undergoing breast biopsy. The three study groups were: a) those with metastasis identified by ACB, b) those undergoing immediate surgery with positive SNB and c) those undergoing immediate surgery with a negative SNB. US features and the amount of tumour in the ACB specimen were assessed by review of US images and pathological reports. BCSS was assessed using Kaplan Meier survival curves. RESULTS: 967 patients were included, with mean follow-up of 6.0 yrs. There were 90 breast cancer deaths: 26% of those with a positive ACB, 11% with a positive SNB and 4% of those with a negative SNB. BCSS was significantly different between the groups (p < 0.001) with hazard ratio, compared with the negative SNB group, of 7.8 (95% CI 4.4-13.7) for patients with positive ACB and 2.5 (95% CI 1.3-4.6) for positive SNB. Axillary US findings and assessment of the amount of tumour in the ACB did not influence survival. CONCLUSION: This study suggests that women with a positive ACB have a worse BCSS compared to those with a positive SNB. This should be borne in mind when systemic therapy is being considered.

Mode of presentation and skin thickening on ultrasound may predict nodal burden in breast cancer patients with a positive axillary core biopsy.

OBJECTIVE: A number of pre-operative factors predicting nodal burden in females with breast cancer have recently been identified. The aim of this study is to assess if these factors independently influence nodal burden in females with a positive axillary core biopsy. METHODS: All node positive patients detected on axillary core biopsy were identified in our cancer audit database. Mode of presentation, age, core tumour grade, core tumour type, ER and HER2 status were evaluated. Tumours were assessed for ultrasound size, distance of tumour-to-skin, presence of invasion of skin and diffuse skin thickening. Axillary lymph nodes were assessed for cortical thickness and presence of ultrasound replaced nodes. Statistical significance was ascertained using univariate logistic regression. A predictive model was produced following a multiple logistic regression model incorporating cross-validation and assessed using receiving operating characteristic curve. RESULTS: 115 patients' data were analysed. Patients referred because of symptoms (70% vs 38%, p = 0.005), and those with ultrasound skin thickening (87% vs 59%, p = 0.055) have higher nodal burden than those referred from screening or without skin thickening. These factors were significant after multivariate analysis. The final predictive model included mode of presentation, ultrasound tumour size, cortical thickness and presence of ultrasound skin thickening. The area under curve is 0.77. CONCLUSION: We have shown that mode of presentation and ultrasound skin thickening are independent predictors of high nodal burden at surgery. A model has been developed to predict nodal burden pre-operatively, which may lead to avoidance of axillary node clearance in patients with lower nodal burden. ADVANCES IN KNOWLEDGE: Method of presentation and skin involvement/proximity to skin by the primary tumour are known to influence outcome and nodal involvement respectively but have not been studied with regard to nodal burden. We have shown that mode of presentation and skin thickening at ultrasound are independent predictors of high nodal burden at surgery.

∆Np63/p40 correlates with the location and phenotype of basal/mesenchymal cancer stem-like cells in human ER+ and HER2+ breast cancers.

ΔNp63, also known as p40, regulates stemness of normal mammary gland epithelium and provides stem cell characteristics in basal and HER2-driven murine breast cancer models. Whilst ΔNp63/p40 is a characteristic feature of normal basal cells and basal-type triple-negative breast cancer, some receptor-positive breast cancers express ΔNp63/p40 and its overexpression imparts cancer stem cell-like properties in ER+ cell lines. However, the incidence of ER+ and HER2+ tumours that express ΔNp63/p40 is unclear and the phenotype of ΔNp63/p40+ cells in these tumours remains uncertain. Using immunohistochemistry with p63 isoform-specific antibodies, we identified a ΔNp63/p40+ tumour cell subpopulation in 100 of 173 (58%) non-triple negative breast cancers and the presence of this population associated with improved survival in patients with ER- /HER2+ tumours (p = 0.006). Furthermore, 41% of ER+ /PR+ and/or HER2+ locally metastatic breast cancers expressed ΔNp63/p40, and these cells commonly accounted for <1% of the metastatic tumour cell population that localised to the tumour/stroma interface, exhibited an undifferentiated phenotype and were CD44+ /ALDH- . In vitro studies revealed that MCF7 and T47D (ER+ ) and BT-474 (HER2+ ) breast cancer cell lines similarly contained a small subpopulation of ΔNp63/p40+ cells that increased in mammospheres. In vivo, MCF7 xenografts contained ΔNp63/p40+ cells with a similar phenotype to primary ER+ cancers. Consistent with tumour samples, these cells also showed a distinct location at the tumour/stroma interface, suggesting a role for paracrine factors in the induction or maintenance of ΔNp63/p40. Thus, ΔNp63/p40 is commonly present in a small population of tumour cells with a distinct phenotype and location in ER+ and/or HER2+ human breast cancers.

Breast MRI and tumour biology predict axillary lymph node response to neoadjuvant chemotherapy for breast cancer.

BACKGROUND: In patients who have had axillary nodal metastasis diagnosed prior to neoadjuvant chemotherapy for breast cancer, there is little consensus on how to manage the axilla subsequently. The aim of this study was to explore whether a combination of breast magnetic resonance imaging (MRI) assessed response and primary tumour pathology factors could identify a subset of patients that might be spared axillary node clearance. METHODS: A retrospective data analysis was performed of patients with core biopsy-proven axillary nodal metastasis prior to commencement of neoadjuvant chemotherapy (NAC) who had subsequent axillary node clearance (ANC) at definitive breast surgery. Breast tumour and axillary response at MRI before, during and on completion of NAC, core biopsy tumour grade, tumour type and immunophenotype were correlated with pathological response in the breast and the number of metastatic nodes in the ANC specimens. RESULTS: Of 87 consecutive patients with MRI at baseline, interim and after neoadjuvant chemotherapy who underwent ANC at time of breast surgery, 33 (38%) had no residual macrometastatic axillary disease, 28 (32%) had 1-2 metastatic nodes and 26 (30%) had more than 2 metastatic nodes. Factors that predicted axillary nodal complete response were MRI complete response in the breast (p < 0.0001), HER2 positivity (p = 0.02) and non-lobular tumour type (p = 0.015). CONCLUSION: MRI assessment of breast tumour response to NAC and core biopsy factors are predictive of response in axillary nodes, and can be used to guide decision making regarding appropriate axillary surgery.

Are baseline ultrasound and mammographic features associated with rates of pathological completes response in patients receiving neoadjuvant chemotherapy for breast cancer?

BACKGROUND: Increasing numbers of breast cancer patients receive neoadjuvant chemotherapy (NACT). We seek to investigate whether baseline mammographic and ultrasound features are associated with complete pathological response (pCR) after NACT. METHODS: A database of NACT patients was reviewed. Baseline imaging parameters assessed were ultrasound: posterior effect; echo pattern; margin and lesion diameter; mammography: spiculation and microcalcification. Core biopsy grade and immunophenotype were documented. Data were analysed for the whole study group and by immunophenotype. RESULTS: Of the 222 cancers, 83 (37%) were triple negative (TN), 61 (27%) ER positive/HER-2 negative and 78 (35%) HER-2 positive. A pCR occurred in 46 of 222 cancers (21%). For the whole group, response was associated with high core biopsy grade (grade 3 vs. grade 1 or 2) (26% vs. 9%, p = 0.0044), absence of posterior shadowing on ultrasound (26% vs. 10%, p <  0.001) and the absence of mammographic spiculation (26 vs. 6%, p <  0.001). Within the HER-2 positive group; the absence of shadowing and spiculation remained highly associated with pCR, in addition to small ultrasound size (AUC = 0.71, p < 0.001) and the absence of microcalcification (39% vs. 21%, p < 0.02). On multivariable analysis absence of spiculation and core grade remained significant for the whole cohort, size and absence of spiculation remained significant for HER-2 positive tumours. No feature predicted pCR in TN tumours. CONCLUSION: A pCR is less likely when there is mammographic spiculation. Small ultrasound size is associated with pCR in HER-2 positive tumours. These findings may be helpful when discussing NACT and surgical options with patients. TRIAL REGISTRATION: UK Clinical Trials Gateway: registration number 16712.

The circular RNome of primary breast cancer.

Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R < 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.

Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected.

Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1.

Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.

A comparison of the imaging features of pleomorphic and classical invasive lobular carcinoma.

PURPOSE: Pleomorphic invasive lobular carcinoma (pILC) is a distinct morphological variant of ILC with a poorer prognosis than classical ILC (cILC). The aim of this study was to ascertain whether the conventional imaging appearances of the two entities differ. METHODS: A single-center retrospective review of conventional imaging was undertaken in 150 consecutive patients with histopathologically confirmed ILC (38 pILC; 112 cILC) between April 2010 and July 2015. Mammographic and sonographic findings were evaluated using the BI-RADS lexicon by a radiologist blinded to pathology, and the findings in the two groups were compared. The degree of discrepancy between imaging and pathological sizing in the two groups was evaluated. RESULTS: Lesions were mammographically occult in 11% of pILC and 14% of cILC (p = 0.56). On mammography, skin or trabecular thickening and microcalcification were commoner in pILC than cILC (13% vs. 1%, p < 0.01; 25% vs. 5%, p < 0.01). Architectural distortion was more frequent in cILC than pILC (26% vs. 9%, p = 0.01). On ultrasound, pILC more frequently exhibited mixed echogenicity (28% vs. 13%; p = 0.04), skin thickening, subcutaneous or parenchymal edema (8% vs. 0%; p = 0.02), echogenic surrounding fat (33% vs. 9%; p < 0.01), and posterior acoustic enhancement (10% vs. 1%; p = 0.02) than cILC. CILC was more frequently manifested as a focal area of altered echogenicity (24% vs. 8%; p = 0.04). Mean elastography stiffness was higher for pILC (174.8 vs. 124.6 kPa; p = 0.02). Imaging-pathological size disparity was similar for both subtypes. CONCLUSION: There are differences in the imaging features between pILC and cILC which reflect the more aggressive nature of pILC.

Non-histopathological parameters associated with upgrade of breast tumours yielding a core biopsy report of histological grade 2 ductal no special type to grade 3 on excision.

PURPOSE: The aim of the study was to identify clinical, radiological and immuno-histochemical factors that may help predict upgrade of invasive ductal cancers of no special type (IDC-NST) with a core biopsy grade of 2 to grade 3 on final histology. METHODS: A prospectively maintained database of ultrasound visible solid masses was used to identify lesions yielding a core biopsy result of IDC-NST grade 2 who underwent immediate surgery yielding a grade 2 or grade 3 tumour. Associations were sought between the source of patient (screening/symptomatic), core biopsy receptor status and imaging findings and the grade of the excision specimen tumour. Statistical analysis, which included the chi-squared test, ROC curves and Cox regression analysis, was used to compare upgrade vs no upgrade for each factor. RESULTS: 463 IDC-NST breast cancers of core biopsy grade 2 gave 344 grade 2 and 119 grade 3 tumours at excision. Factors significantly associated with upgrade were large ultrasound (US) size, hyperechogencity, stiffness at shearwave elastography (SWE), calcification on mammography and oestrogen receptor (ER) and progesterone receptor (PR) negativity. Patient source, Human epidermal growth factor receptor 2 (HER-2) status, ultrasound (US) distal effect and mammographic spiculation were not significantly associated with chance of upgrade. On multivariate analysis, only US size maintained statistical significance. CONCLUSION: Oncologists and surgeons should be aware that lesions with a core biopsy diagnosis of grade 2 IDC-NST measuring over 15 mm on US have a 37% chance of being grade 3 on excision and this should be considered when deciding pre-operative management.

Pre-operative stromal stiffness measured by shear wave elastography is independently associated with breast cancer-specific survival.

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.

Breast cancer: influence of tumour volume estimation method at MRI on prediction of pathological response to neoadjuvant chemotherapy.

OBJECTIVE: Does method of tumour volume measurement on MRI influence prediction of treatment outcome in patients with primary breast cancer undergoing neoadjuvant chemotherapy (NAC)?. METHOD: The study comprised of 136 women with biopsy-proven breast cancer scheduled for MRI monitoring during NAC treatment. Dynamic contrast-enhanced images were acquired at baseline (pre-NAC) and interim (post three NAC cycles) time points. Functional tumour volumes (FTVs), automatically derived using vendor software and enhancing tumour volumes (ETVs), user-derived using a semi-automated thresholding technique, were calculated at each time point and percentage changes calculated. Response, assessed using residual cancer burden (RCB) score on surgically resected specimens, was compared statistically with volumetric changes and receiver operating characteristic analysis performed. RESULTS: Mean volumetric differences for each RCB response category were (FTV/ETV): pathological complete response (pCR) 95.5/96.8%, RCB-I 69.8/66.7%, RCB-II 64.0/65.5%, RCB-III 25.4/24.0%. Differences were significant between pCR and RCB-II/RCB-III categories (p < 0.040; unpaired t-test) using FTV measures and between pCR and RCB-I/RCB-II/RCB-III categories (p < 0.006; unpaired t-test) when ETV was used. Receiver operating characteristic analysis for pCR identification post-NAC yielded area under the curve for FTV/ETV of 0.834/0.920 respectively. Sensitivity and specificity for FTV was 80.0 and 76.8% for FTV and 81.0 and 91.8% for ETV. CONCLUSION: ETV changes can identify patients likely to achieve a complete response to NAC. Potentially, this could impact patient management regarding the possible avoidance of post-NAC surgery. Advances in Knowledge: Interim changes in ETV are more useful than FTV in predicting final pathological response to NAC. ETV differentiates patients who will achieve a complete response from those who will have residual disease.

Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy for Primary Breast Cancer Comparing Interim Ultrasound, Shear Wave Elastography and MRI.

BACKGROUND: Prediction of pathological complete response (pCR) of primary breast cancer to neoadjuvant chemotherapy (NACT) may influence planned surgical approaches in the breast and axilla. The aim of this project is to assess the value of interim shear wave elastography (SWE), ultrasound (US) and magnetic resonance imaging (MRI) after 3 cycles in predicting pCR. METHODS: 64 patients receiving NACT had baseline and interim US, SWE and MRI examinations. The mean lesion stiffness at SWE, US and MRI diameter was measured at both time points. We compared four parameters with pCR status: a) Interim mean stiffness ≤ or > 50 kPa; b) Percentage stiffness reduction; c) Percentage US diameter reduction and d) Interim MRI response using RECIST criteria. The Chi square test was used to assess significance. RESULTS: Interim stiffness of ≤ or > 50 kPa gave the best prediction of pCR with pCR seen in 10 of 14 (71 %) cancers with an interim stiffness of ≤ 50 kPa, compared to 7 of 50 (14 %) of cancers with an interim stiffness of > 50 kPa, (p < 0.0001) (sensitivity 59 %, specificity 91 %, PPV 71 %, NPV 86 % and diagnostic accuracy 83 %). Percentage reduction in stiffness was the next best parameter (sensitivity 59 %, specificity 85 %, p < 0.0004) followed by reduction in MRI diameter of > 30 % (sensitivity 50 % and specificity 79 %, p = 0.03) and % reduction in US diameter (sensitivity 47 %, specificity 81 %, p = 0.03). Similar results were obtained from ROC analysis. CONCLUSION: SWE stiffness of breast cancers after 3 cycles of NACT and changes in stiffness from baseline are strongly associated with pCR after 6 cycles.

Corrigendum: A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.

This corrects the article DOI: 10.1038/ng.3771.