Publications by authors named "Mitch Dowsett"

332 Publications

"Real-world" radiomics from multi-vendor MRI: an original retrospective study on the prediction of nodal status and disease survival in breast cancer, as an exemplar to promote discussion of the wider issues.

Cancer Imaging 2021 May 20;21(1):37. Epub 2021 May 20.

Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.

Background: Most MRI radiomics studies to date, even multi-centre ones, have used "pure" datasets deliberately accrued from single-vendor, single-field-strength scanners. This does not reflect aspirations for the ultimate generalisability of AI models. We therefore investigated the development of a radiomics signature from heterogeneous data originating on six different imaging platforms, for a breast cancer exemplar, in order to provide input into future discussions of the viability of radiomics in "real-world" scenarios where image data are not controlled by specific trial protocols but reflective of routine clinical practice.

Methods: One hundred fifty-six patients with pathologically proven breast cancer underwent multi-contrast MRI prior to neoadjuvant chemotherapy and/or surgery. From these, 92 patients were identified for whom T2-weighted, diffusion-weighted and contrast-enhanced T1-weighted sequences were available, as well as key clinicopathological variables. Regions-of-interest were drawn on the above image types and, from these, semantic and calculated radiomics features were derived. Classification models using a variety of methods, both with and without recursive feature elimination, were developed to predict pathological nodal status. Separately, we applied the same methods to analyse the information carried by the radiomic features regarding the originating scanner type and field strength. Repeated, ten-fold cross-validation was employed to verify the results. In parallel work, survival modelling was performed using random survival forests.

Results: Prediction of nodal status yielded mean cross-validated AUC values of 0.735 ± 0.15 (SD) for clinical variables alone, 0.673 ± 0.16 (SD) for radiomic features only, and 0.764 ± 0.16 (SD) for radiomics and clinical features together. Prediction of scanner platform from the radiomics features yielded extremely high values of AUC between 0.91 and 1 for the different classes examined indicating the presence of confounding features for the nodal status classification task. Survival analysis, gave out-of-bag prediction errors of 19.3% (clinical features only), 36.9-51.8% (radiomic features from different combinations of image contrasts), and 26.7-35.6% (clinical plus radiomics features).

Conclusions: Radiomic classification models whose predictive ability was consistent with previous single-vendor, single-field strength studies have been obtained from multi-vendor, multi-field-strength data, despite clear confounding information being present. However, our sample size was too small to obtain useful survival modelling results.
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http://dx.doi.org/10.1186/s40644-021-00406-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136229PMC
May 2021

Response to Zhang and Yang.

J Natl Cancer Inst 2021 May 18. Epub 2021 May 18.

University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1093/jnci/djab094DOI Listing
May 2021

Abiraterone in patients with recurrent epithelial ovarian cancer: principal results of the phase II Cancer of the Ovary Abiraterone (CORAL) trial (CRUK - A16037).

Ther Adv Med Oncol 2020 29;12:1758835920975352. Epub 2020 Dec 29.

Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.

Background: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC.

Patients & Methods: CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks.

Results: A total of 42 patients were recruited; median age 65 (range 34-85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays.

Conclusions: CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation.

Trial Registration: CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050.
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http://dx.doi.org/10.1177/1758835920975352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013695PMC
December 2020

Unmasking the immune microecology of ductal carcinoma in situ with deep learning.

NPJ Breast Cancer 2021 Mar 1;7(1):19. Epub 2021 Mar 1.

Centre for Evolution and Cancer, Institute of Cancer Research, London, UK.

Despite increasing evidence supporting the clinical relevance of tumour infiltrating lymphocytes (TILs) in invasive breast cancer, TIL spatial variability within ductal carcinoma in situ (DCIS) samples and its association with progression are not well understood. To characterise tissue spatial architecture and the microenvironment of DCIS, we designed and validated a new deep learning pipeline, UNMaSk. Following automated detection of individual DCIS ducts using a new method IM-Net, we applied spatial tessellation to create virtual boundaries for each duct. To study local TIL infiltration for each duct, DRDIN was developed for mapping the distribution of TILs. In a dataset comprising grade 2-3 pure DCIS and DCIS adjacent to invasive cancer (adjacent DCIS), we found that pure DCIS cases had more TILs compared to adjacent DCIS. However, the colocalisation of TILs with DCIS ducts was significantly lower in pure DCIS compared to adjacent DCIS, which may suggest a more inflamed tissue ecology local to DCIS ducts in adjacent DCIS cases. Our study demonstrates that technological developments in deep convolutional neural networks and digital pathology can enable an automated morphological and microenvironmental analysis of DCIS, providing a new way to study differential immune ecology for individual ducts and identify new markers of progression.
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http://dx.doi.org/10.1038/s41523-020-00205-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921670PMC
March 2021

A simple digital image analysis system for automated Ki67 assessment in primary breast cancer.

Histopathology 2021 Feb 15. Epub 2021 Feb 15.

Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital and The Institute of Cancer Research, London, UK.

Aims: Ki67 is a well-established immunohistochemical marker associated with cell proliferation that has prognostic and predictive value in breast cancer. Quantitative evaluation of Ki67 is traditionally performed by assessing stained tissue slides with light microscopy. Automated image analysis systems have become available and, if validated, could provide greater standardisation and improved precision of Ki67 scoring. Here, we aimed to evaluate the use of the Cognition Master Professional Suite (CogM) image analysis software, which is a simple system for scoring Ki67 in primary breast cancer samples.

Methods And Results: Sections from 94 core-cut biopsies, 20 excision specimens and 29 pairs of core-cut biopsies and excision specimens were stained for Ki67 with MIB1 antibody and the Dako EnVision FLEX Detection System. Stained slides were scanned to convert them to digital data. Computer-based Ki67 scoring was performed with CogM. Manual Ki67 scoring assessment was conducted on previously stained sections from the same biopsies with a clinically validated system that had been calibrated against the risk of recurrence. A high correlation between manual and digital scores was observed [r  = 0.92, 95% confidence interval (CI) 0.87-0.94, P < 0.0001; r  = 0.95, 95% CI 0.86-0.98, P < 0.0001] and there was no significant bias between them (P = 0.45). There was also a high correlation of Ki67 scores between paired core-cut biopsies and excision specimens when CogM was used (r = 0.78, 95% CI 0.59-0.89, P < 0.0001).

Conclusions: CogM image analysis allows for standardised automated Ki67 scoring that accurately replicates previously clinically validated and calibrated manual scores.
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http://dx.doi.org/10.1111/his.14355DOI Listing
February 2021

Development and validation for research assessment of Oncotype DX® Breast Recurrence Score, EndoPredict® and Prosigna®.

NPJ Breast Cancer 2021 Feb 12;7(1):15. Epub 2021 Feb 12.

Clinical Trials and Statistics Unit (ICR-CTSU), Division of Clinical Studies, The Institute of Cancer Research, London, UK.

Multi-gene prognostic signatures including the Oncotype® DX Recurrence Score (RS), EndoPredict® (EP) and Prosigna® (Risk Of Recurrence, ROR) are widely used to predict the likelihood of distant recurrence in patients with oestrogen-receptor-positive (ER+), HER2-negative breast cancer. Here, we describe the development and validation of methods to recapitulate RS, EP and ROR scores from NanoString expression data. RNA was available from 107 tumours from postmenopausal women with early-stage, ER+, HER2- breast cancer from the translational Arimidex, Tamoxifen, Alone or in Combination study (TransATAC) where previously these signatures had been assessed with commercial methodology. Gene expression was measured using NanoString nCounter. For RS and EP, conversion factors to adjust for cross-platform variation were estimated using linear regression. For ROR, the steps to perform subgroup-specific normalisation of the gene expression data and calibration factors to calculate the 46-gene ROR score were assessed and verified. Training with bootstrapping (n = 59) was followed by validation (n = 48) using adjusted, research use only (RUO) NanoString-based algorithms. In the validation set, there was excellent concordance between the RUO scores and their commercial counterparts (r(RS) = 0.96, 95% CI 0.93-0.97 with level of agreement (LoA) of -7.69 to 8.12; r(EP) = 0.97, 95% CI 0.96-0.98 with LoA of -0.64 to 1.26 and r(ROR) = 0.97 (95% CI 0.94-0.98) with LoA of -8.65 to 10.54). There was also a strong agreement in risk stratification: (RS: κ = 0.86, p < 0.0001; EP: κ = 0.87, p < 0.0001; ROR: κ = 0.92, p < 0.001). In conclusion, the calibrated algorithms recapitulate the commercial RS and EP scores on individual biopsies and ROR scores on samples based on subgroup-centreing method using NanoString expression data.
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http://dx.doi.org/10.1038/s41523-021-00216-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881187PMC
February 2021

Assessment of Ki67 in Breast Cancer: Updated Recommendations from the International Ki67 in Breast Cancer Working Group.

J Natl Cancer Inst 2020 Dec 28. Epub 2020 Dec 28.

University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.

Ki67 immunohistochemistry, commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 immunohistochemistry analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, pre-analytical handling considerations are critical. 2) A standardized visual scoring method has been established and is recommended for adoption. 3) Participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity. 4) The IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable ER-positive and HER2-negative patients, to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 ≤ 5% or ≥ 30% can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to pre-analytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I/II breast cancer. Further development of automated scoring might help to overcome some current limitations.
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http://dx.doi.org/10.1093/jnci/djaa201DOI Listing
December 2020

UK NEQAS ICC & ISH Ki-67 Data Reveal Differences in Performance of Primary Antibody Clones.

Appl Immunohistochem Mol Morphol 2021 02;29(2):86-94

UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation.

We examined data from 374 laboratories staining for Ki-67 as part of external quality assessment over 8 runs between 2013 and 2017 (total data sets=2601). One of 5 primary antibodies was used for 94.8% of submissions, with MIB-1 (Agilent Dako) comprising 58.8% of the total. Examining assessment score as a continuous variable showed the 30-9 (Ventana) and K2 (Leica Biosystems) clones were associated with the highest mean scores (17.0; 95% confidence interval, 16.8-17.2 and 16.3; 95% confidence interval, 15.9-16.6, respectively). Stain quality was not significantly different between them. Both were associated with significantly better staining compared with MIB-1 (Agilent Dako), MM1 (Leica Biosystems), and SP6 from various suppliers (P<0.05). Similarly, categorical assessment of "Good" versus "Not good" staining quality showed that the 30-9 and K2 clones were both significantly associated with "Good" staining (both P<0.001). Other methodological parameters were examined for significant primary antibody-specific effects; none were seen for 30-9, K2, or SP6. The MM1 clone was more likely to be associated with good quality staining when it was used with Leica Biosystems sourced antigen retrieval, detection, and platform, all statistically significant at P<0.01. MIB-1 was more likely to be associated with good quality staining results when it was used with Agilent Dako antigen retrieval, detection, and staining platforms (P<0.0001), and less likely at the same significance level when used with Leica Biosystems reagents and equipment. The data presented here show the importance of not just primary antibody choice but also matching that choice to other methodological factors.
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http://dx.doi.org/10.1097/PAI.0000000000000899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993918PMC
February 2021

Calibration of CTS5 in Women With Early Estrogen Receptor-Positive Breast Cancer.

J Clin Oncol 2021 Feb 16;39(4):338-339. Epub 2020 Dec 16.

Mitch Dowsett, PhD, Ralph Lauren Centre for Breast Cancer Research, Royal Marden Hospital, London, UK and Ivana Sestak, PhD and Jack Cuzick, PhD, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.1200/JCO.20.02551DOI Listing
February 2021

Clinical validity of clinical treatment score 5 (CTS5) for estimating risk of late recurrence in unselected, non-trial patients with early oestrogen receptor-positive breast cancer.

Breast Cancer Res Treat 2021 Feb 21;186(1):115-123. Epub 2020 Nov 21.

Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.

Purpose: Clinical Treatment Score at 5 years (CTS5) is a prognostic tool to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with oestrogen receptor-positive (ER-positive) breast cancer.

Methods: The validity of CTS5 was tested in a retrospective cohort of patients diagnosed with early ER-positive breast cancer. The primary endpoint was DR in years 5-10. The primary analysis cohort consisted of postmenopausal women, with premenopausal women as a secondary analysis cohort. Cox regression models were used to determine the prognostic value of CTS5 and Kaplan-Meier curves were used with associated 10-year DR risks (%).

Results: 2428 women were included with a median follow-up of 13.4 years. The CTS5 was significantly prognostic in both postmenopausal (N = 1662, HR = 2.18 95% CI (1.78-2.67)) and premenopausal women (N = 766, HR = 1.84 95% CI (1.32-2.56)). The 10-year DR risks were 2.9% (1.9-4.5), 7.2% (5.3-9.9), and 12.9% (10.0-16.7) for low, intermediate and high risk in postmenopausal women and 3.8% (2.2-6.7), 6.9% (4.4-10.8), and 11.1% (7.4-16.5) in premenopausal women, respectively. The number of observed DRs was significantly greater than expected in those predicted to be at high risk by CTS5 but this discordance was lost when those receiving more than 60 months of endocrine therapy were excluded.

Conclusions: The CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected postmenopausal patients but less so in premenopausal patients. Calibration of the CTS5 was good in patients who did not receive extended endocrine therapy. The CTS5 low-risk cohort has risk of DR so low as to not warrant extended endocrine therapy.
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http://dx.doi.org/10.1007/s10549-020-06013-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940308PMC
February 2021

Tamoxifen related side effects and their impact on breast cancer incidence: A retrospective analysis of the randomised IBIS-I trial.

Breast 2020 Dec 31;54:216-221. Epub 2020 Oct 31.

Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Charterhouse Square, Queen Mary University London, London, EC1M 6BQ, UK. Electronic address:

Background: Studies in the adjuvant setting have shown that endocrine therapy related side effects predict breast cancer recurrence risk. Here, we assess the relationship between early reported side effects and incidence of breast cancer in women randomised to tamoxifen for cancer prevention in the International Breast Intervention Study (IBIS)-I trial.

Methods: Women randomised to tamoxifen in the IBIS-I trial and for whom side effect status was known at the 6-month follow-up visit were included in this analysis. Side effects included in this analysis were hot flushes, vaginal discharge, and vaginal dryness. The primary endpoint was all breast cancer and secondary endpoint was oestrogen receptor (ER) positive breast cancer. Cox proportional hazard models were used to investigate breast cancer incidence in the tamoxifen group with and without side effects reported within 6 months of randomisation.

Results: Women randomised to tamoxifen and reporting hot flushes at the 6-month follow-up visit had a non-statistically significant increase in breast cancer compared to those without hot flushes (HR = 1.26 (0.98-1.62), P = 0.08). A significant higher breast cancer risk was observed for postmenopausal women who reported hot flushes at the 6-month follow-up visit compared to those without hot flushes (HR = 1.59 (1.12-2.26), P = 0.01). A higher risk was observed for ER-positive breast cancer in postmenopausal women (HR = 1.81 (1.19-2.74), P = 0.01). No significant associations between gynaecological side effects and breast cancer occurrence was observed.

Conclusions: Overall, no association between side effects reported at 6 months and subsequent breast cancer occurrence was observed. Some side effects might be useful markers for breast cancer occurrence in postmenopausal women.
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http://dx.doi.org/10.1016/j.breast.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649356PMC
December 2020

Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial.

Lancet Oncol 2020 11;21(11):1443-1454

The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.

Background: Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki67) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67). The POETIC trial aimed to test these two hypotheses.

Methods: POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.

Findings: Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67 and Ki67 (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67 and low Ki67 (high-low) and 21·5% (17·1-27·0) with high Ki67 and Ki67 (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported.

Interpretation: POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67 or low POAI-induced Ki67 do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki67 remains high might benefit from further adjuvant treatment or trials of new therapies.

Funding: Cancer Research UK.
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http://dx.doi.org/10.1016/S1470-2045(20)30458-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606901PMC
November 2020

Molecular Drivers of Onco DX, Prosigna, EndoPredict, and the Breast Cancer Index: A TransATAC Study.

J Clin Oncol 2021 Jan 27;39(2):126-135. Epub 2020 Oct 27.

The Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, United Kingdom.

Purpose: The Onco DX Recurrence Score (RS), Prosigna Prediction Analysis of Microarray 50 (PAM50) Risk of Recurrence (ROR), EndoPredict (EP), and Breast Cancer Index (BCI) are used clinically for estimating risk of distant recurrence for patients receiving endocrine therapy. Discordances in estimates occur between them. We aimed to identify the molecular features that drive the tests and lead to these differences.

Patients And Methods: Analyses for RS, ROR, EP, and BCI were conducted by the manufacturers in the TransATAC sample collection that consisted of the tamoxifen or anastrozole arms of the ATAC trial. Estrogen receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative cases without chemotherapy treatment were included in which all four tests were available (n = 785). Clinicopathologic features included in some tests were excluded from the comparisons. Estrogen, proliferation, invasion, and HER2 module scores from RS were used to characterize the respective molecular features. Spearman correlation and analysis of variance tests were applied.

Results: There were moderate to strong correlations among the four molecular scores (ρ = 0.63-0.74) except for RS versus ROR (ρ = 0.32) and RS versus BCI (ρ = 0.35). RS had strong negative correlation with its estrogen module (ρ = -0.79) and moderate positive correlation with its proliferation module (ρ = 0.36). RS's proliferation module explained 72.5% of ROR's variance, while the estrogen module explained only 0.6%. Most of EP's and BCI's variation was accounted for by the proliferation module (50.0% and 54.3%, respectively) and much less by the estrogen module (20.2% and 2.7%, respectively).

Conclusion: In contrast to common understanding, RSs are determined more strongly by estrogen-related features and only weakly by proliferation markers. However, the EP, BCI, and particularly ROR scores are determined largely by proliferative features. These relationships help to explain the differences in the prognostic performance of the tests.
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http://dx.doi.org/10.1200/JCO.20.00853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078458PMC
January 2021

Prognostic Value of EndoPredict in Women with Hormone Receptor-Positive, HER2-Negative Invasive Lobular Breast Cancer.

Clin Cancer Res 2020 09 19;26(17):4682-4687. Epub 2020 Jun 19.

Medical University of Vienna, Department of Surgery and Comprehensive Cancer Centre, Vienna, Austria.

Purpose: Invasive lobular carcinoma (ILC) accounts for approximately 5%-15% of all invasive breast cancer cases. Most of the correlations between multigene assays and patient outcome were derived from studies based on patients with invasive ductal carcinoma (IDC) or without distinction between the subtypes. Here, we investigate the prognostic value of EndoPredict (EPclin) in a large cohort of ILCs pooled from three phase III randomized trials (ABCSG-6, ABCSG-8, TransATAC).

Experimental Design: The primary objective of this analysis was to determine the prognostic value of EPclin for distant recurrence (DR) in years 0-10 in postmenopausal women with ILC. The primary outcome was DR.

Results: 470 women (17.9%) presented with ILC, 1,944 (73.9%) with IDC, and 216 (8.2%) with other histologic types. EPclin was highly prognostic in women with ILC [HR = 3.32 (2.54-4.34)] and provided more prognostic value than the Clinical Treatment Score [CTS; HR = 2.17 (1.73-2.72)]. 63.4% of women were categorized into the low EPclin risk group and they had a 10-year DR of 4.8% (2.7-8.4) compared with 36.6% of women in the high-risk group with a 10-year DR risk of 26.6% (20.0-35.0). EPclin also provided highly prognostic information in women with node-negative disease [HR = 2.56 (1.63-4.02)] and node-positive disease [HR = 3.70 (2.49-5.50)].

Conclusions: EPclin provided highly significant prognostic value and significant risk stratification for women with ILC. Ten-year DR risk in the EPclin low-risk groups were similar between ILC and IDC. Our results show that EPclin is informative in women with ILC and suggest that it is equally valid in both histologic subtypes.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0260DOI Listing
September 2020

Evidence-based guidelines for managing patients with primary ER+ HER2- breast cancer deferred from surgery due to the COVID-19 pandemic.

NPJ Breast Cancer 2020 8;6:21. Epub 2020 Jun 8.

West German Study Group, Mönchengladbach, Germany.

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6) (ii) a biopsy for Ki67 analysis (on-treatment Ki67) could be considered after 2-4 weeks of NeoET (a: ER 7 or 8 and PgR <6 or b: ER 6 or 7 and PgR ≥6) or (iii) NeoET is an acceptable course of action (ER 8 and PgR ≥6). Cut-offs for percentage of cells positive are also given. For group (ii), a high early on-treatment level of Ki67 (>10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis.
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http://dx.doi.org/10.1038/s41523-020-0168-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280290PMC
June 2020

Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor-Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials.

Clin Cancer Res 2020 10 16;26(19):5172-5177. Epub 2020 Jun 16.

British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

Purpose: mutations are acquired frequently in hormone receptor-positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane.

Experimental Design: The phase III EFECT and SoFEA trials randomized patients with hormone receptor-positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for mutations by digital PCR. The primary objectives were to assess the impact of mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies.

Results: mutations were detected in 30% (151/383) baseline samples. In patients with mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0-2.6] on exemestane and 3.9 months (95% CI, 3.0-6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39-0.89; = 0.01). In patients without mutations detected, PFS was 4.8 months (95% CI, 3.7-6.2) on exemestane and 4.1 months (95% CI, 3.6-5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81-1.37; = 0.69). There was an interaction between mutation and treatment ( = 0.02). Patients with mutation detected had 1-year OS of 62% (95% CI, 45%-75%) on exemestane and 80% (95% CI, 68%-87%) on fulvestrant ( = 0.04; restricted mean survival analysis). Patients without mutations detected had 1-year OS of 79% (95% CI, 71%-85%) on exemestane and 81% (95% CI, 74%-87%) on fulvestrant ( = 0.69).

Conclusions: Detection of mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0224DOI Listing
October 2020

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.

Nat Commun 2020 05 29;11(1):2662. Epub 2020 May 29.

Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, CB2 0XZ, United Kingdom.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.
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http://dx.doi.org/10.1038/s41467-020-16142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260192PMC
May 2020

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations.

JNCI Cancer Spectr 2019 Dec 10;3(4):pkz050. Epub 2019 Aug 10.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor-positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor-positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.
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http://dx.doi.org/10.1093/jncics/pkz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049988PMC
December 2019

Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions.

JNCI Cancer Spectr 2019 Dec 10;3(4):pkz049. Epub 2019 Aug 10.

Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.
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http://dx.doi.org/10.1093/jncics/pkz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050024PMC
December 2019

Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.

Oncogene 2020 06 19;39(25):4781-4797. Epub 2020 Apr 19.

Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, SW7 3RP, UK.

Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of 'classical' oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M-checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER and RB1 CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition.
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http://dx.doi.org/10.1038/s41388-020-1284-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299844PMC
June 2020

Correction to: Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.

Breast Cancer Res 2020 Jan 31;22(1):14. Epub 2020 Jan 31.

Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.

After publication of the original article [1], we were notified that an author's surname has been erroneously spelled. Elisabetta Maragoni's family name should be replaced with Marangoni.
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http://dx.doi.org/10.1186/s13058-020-1254-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993431PMC
January 2020

Impact of aromatase inhibitor treatment on global gene expression and its association with antiproliferative response in ER+ breast cancer in postmenopausal patients.

Breast Cancer Res 2019 12 31;22(1). Epub 2019 Dec 31.

Breast Cancer Now Research Centre, ICR, London, UK.

Background: Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance.

Methods: Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (control n = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67.

Results: High baseline ESR1 expression associated with better AI response in HER2+ tumours but not HER2- tumours. In HER2- tumours, baseline expression of 48 genes associated with poor antiproliferative response (p < 0.005) including PERP and YWHAQ, the two most significant, and the transcription co-regulators (SAP130, HDAC4, and NCOA7) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling (ERBB2-GS, RET/GDNF-GS, and IGF-1-GS), and immune activity (STAT1-GS) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2- and HER2+ patients.

Conclusions: There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors.

Trial Registration: ISRCTN, ISRCTN63882543, registered on 18 December 2007.
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http://dx.doi.org/10.1186/s13058-019-1223-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938628PMC
December 2019

Use of anastrozole for breast cancer prevention (IBIS-II): long-term results of a randomised controlled trial.

Lancet 2020 01 12;395(10218):117-122. Epub 2019 Dec 12.

Prevent Breast Cancer Unit, Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust, Manchester, UK.

Background: Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period.

Methods: IBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.

Findings: 3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105-156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39-0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27-0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45-0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33-0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22-0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78-0·65, p<0·0001). No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69-1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo). A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57-0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.

Interpretation: This analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.

Funding: Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, Sanofi Aventis, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(19)32955-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961114PMC
January 2020

Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer.

Breast Cancer Res 2019 12 4;21(1):135. Epub 2019 Dec 4.

Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.

Background: Endocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic. Cross-talk between ER and PI3K/AKT/mTORC has been associated with ligand-independent transcription of ER. We have previously reported the anti-proliferative effects of the combination of everolimus (an mTORC1 inhibitor) with endocrine therapy in resistance models, but potential routes of escape via AKT signalling can lead to resistance; therefore, the use of dual mTORC1/2 inhibitors has met with significant interest.

Methods: To address this, we tested the effect of vistusertib, a dual mTORC1 and mTORC2 inhibitor, in a panel of endocrine-resistant and endocrine-sensitive ER+ BC cell lines, with varying PTEN, PIK3CA and ESR1 mutation status. End-points included proliferation, cell signalling, cell cycle and effect on ER-mediated transcription. Two patient-derived xenografts (PDX) modelling endocrine resistance were used to assess the efficacy of vistusertib, fulvestrant or the combination on tumour progression, and biomarker studies were conducted using immunohistochemistry and RNA-seq technologies.

Results: Vistusertib caused a dose-dependent decrease in proliferation of all the cell lines tested and reduced abundance of mTORC1, mTORC2 and cell cycle markers, but caused an increase in abundance of EGFR, IGF1R and ERBB3 in a context-dependent manner. ER-mediated transcription showed minimal effect of vistusertib. Combined therapy of vistusertib with fulvestrant showed synergy in two ER+ PDX models of resistance to endocrine therapy and delayed tumour progression after cessation of therapy.

Conclusions: These data support the notion that models of acquired endocrine resistance may have a different sensitivity to mTOR inhibitor/endocrine therapy combinations.
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http://dx.doi.org/10.1186/s13058-019-1222-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894349PMC
December 2019

Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer.

NPJ Breast Cancer 2019 15;5:42. Epub 2019 Nov 15.

1The Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, Fulham Road, London, UK.

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27-35 and 1-6; low oestradiol and low progesterone), W2 (days 7-16; high oestradiol and low progesterone) and W3 (days 17-26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of , , and ) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including , and , and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3-2.4-fold; FDR 0.016-0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer.
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http://dx.doi.org/10.1038/s41523-019-0138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858333PMC
November 2019

The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.

Cell Rep 2019 10;29(4):889-903.e10

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.
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http://dx.doi.org/10.1016/j.celrep.2019.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874102PMC
October 2019

Validation of the OncoMasTR Risk Score in Estrogen Receptor-Positive/HER2-Negative Patients: A TransATAC study.

Clin Cancer Res 2020 02 22;26(3):623-631. Epub 2019 Oct 22.

Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.

Purpose: To test the validity of OncoMasTR Molecular Score (OMm), OMclin1, and OncoMasTR Risk Score (OMclin2) prognostic scores for prediction of distant recurrence (DR) in estrogen receptor (ER)-positive/HER2-negative breast cancer treated with 5 years' endocrine therapy only and compare their performance with the Oncotype DX Recurrence Score (RS).

Experimental Design: OMm incorporates three master transcription regulator genes. OMclin1 combines OMm, tumor size, grade, and nodal status; OMclin2 incorporates OMm, tumor size, and nodal status. OMclin1 and OMclin2 were evaluated for 646 postmenopausal patients with ER-positive/HER2-negative primary breast cancer with 0-3 involved lymph nodes in TransATAC. Patients were randomized to 5 years' anastrozole or tamoxifen without chemotherapy. RS was available in all cases. We used likelihood ratio-, C-index, and Kaplan-Meier analyses to assess prognostic information.

Results: OMm, OMclin1, and OMclin2 were highly prognostic for prediction of DR in years 0-10 among all patients [likelihood ratio (LR)- = 25.4, 48.7, and 45.0, respectively, all < 0.001; C-index = 0.67, 0.71, and 0.71, respectively], compared with RS (LR- = 18.8; < 0.001; C-index = 0.63). All three scores provided significant additional prognostic value beyond clinical treatment score, Nottingham Prognostic Index, and Ki67. OMclin1 and OMclin2 categorized 190 and 267 node-negative patients as low risk (DR rates: 2.9% and 4.9%, respectively). In comparison, RS categorized 296 node-negative patients as low-risk and 128 patients as intermediate-risk (DR rate: 6.6% and 17.3%, respectively).

Conclusions: OMm, OMclin1, and OMclin2 were highly prognostic for early and late DR in women with early-stage ER-positive breast cancer receiving 5 years' endocrine therapy. In TransATAC, OMclin1 and the OncoMasTR Risk Score (OMclin2) were superior to RS in identifying patients at increased risk of DR.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0712DOI Listing
February 2020

Inactivating Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance.

Clin Cancer Res 2020 02 7;26(3):608-622. Epub 2019 Oct 7.

Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.

Purpose: Advanced breast cancer (ABC) has not been subjected to the same degree of molecular scrutiny as early primary cancer. Breast cancer evolves with time and under the selective pressure of treatment, with the potential to acquire mutations with resistance to treatment and disease progression. To identify potentially targetable mutations in advanced breast cancer, we performed prospective molecular characterization of a cohort of patients with ABC.

Experimental Design: Biopsies from patients with advanced breast cancer were sequenced with a 41 genes targeted panel in the ABC Biopsy (ABC-Bio) study. Blood samples were collected at disease progression for circulating tumor DNA (ctDNA) analysis, along with matched primary tumor to assess for acquisition in ABC in a subset of patients.

Results: We sequenced 210 ABC samples, demonstrating enrichment compared with primary disease for potentially targetable mutations in (in 6.19% of samples), (7.14%), and (8.10%). Of these enriched mutations, we show that mutations were frequently acquired in ABC, not present in the original primary disease. In ER-positive cancer cell line models, loss of resulted in endocrine therapy resistance, through both ER-dependent and -independent mechanisms. NF1 loss promoted ER-independent cyclin D1 expression, which could be therapeutically targeted with CDK4/6 inhibitors . Patients with mutations detected in baseline circulating tumor DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant.

Conclusions: Our research identifies multiple therapeutic opportunities for advanced breast cancer and identifies the previously underappreciated acquisition of mutations.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4044DOI Listing
February 2020

Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors.

Clin Cancer Res 2019 12 23;25(24):7485-7496. Epub 2019 Sep 23.

Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom.

Purpose: To investigate the presence of mutations in primary estrogen-receptor-positive (ER) breast cancer treated with extended (>4 weeks) neoadjuvant (presurgical) aromatase inhibitor (NAI) therapy and to identify patients who may gain less benefit from aromatase inhibition (AI) alone based upon on-treatment changes in gene expression.

Experimental Design: We evaluated ER, progesterone receptor, and Ki67 by immunostaining, mutations by droplet-digital PCR and expression of over 800 key breast cancer genes in paired pre- and post-NAI tumor samples from 87 ER breast cancer patients.

Results: Cell proliferation and estrogen-regulated genes (ERG) remained suppressed in most tumors indicative of persistent response to NAI. Enrichment of mutations was found in five tumors and predominantly in patients receiving therapy for >6 months. -mutant tumors showed increased expression of transcript and limited suppression of ERGs and proliferation-associated genes in response to NAI. wild-type tumors with high residual proliferation (Ki67r ≥10%; 15/87 tumors) showed lower /ER expression pre- and post-therapy and lower ERGs. Tumors with mutations or Ki67r ≥10% showed less inhibition of estrogen response, cell cycle, and E2F-target genes.

Conclusions: Ligand-independent ER signaling, as a result of mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1129DOI Listing
December 2019

Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer.

JAMA Oncol 2019 10;5(10):1473-1478

Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.

Importance: Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.

Objective: To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer.

Design, Setting, And Participants: This prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study.

Interventions: Primary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months.

Main Outcomes And Measures: The primary end point was relapse-free survival analyzed with Cox proportional hazards regression models.

Results: In the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6; P < .001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1; P = .01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis.

Conclusions And Relevance: The findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.
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http://dx.doi.org/10.1001/jamaoncol.2019.1838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681568PMC
October 2019