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Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England’s 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an “FFPEImpact” score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many. Formalin fixation is commonly used in tissue storage; however, this process has traditionally limited downstream whole genome sequencing usage. Here, the authors identify artefactual signatures in FFPE-derived sequencing data and demonstrate the preservation of clinical utility, thus enabling FFPE whole genome sequencing when required.

The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer. In this randomised, open-label, phase 3 trial, we enrolled women (≥18 years) with newly diagnosed HER2-negative early invasive breast cancer (radiological tumour size >20 mm, with or without axillary involvement), at 66 centres in the UK. Patients were randomly assigned via a central computerised minimisation procedure to three cycles of docetaxel (100 mg/m2 once every 21 days) followed by three cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) once every 21 days (D-FEC), without or with four cycles of bevacizumab (15 mg/kg) (Bev+D-FEC). The primary endpoint was pathological complete response, defined as the absence of invasive disease in the breast and axillary lymph nodes, analysed by intention to treat. The trial has completed and follow-up is ongoing. This trial is registered with EudraCT (2008-002322-11), ISRCTN (68502941), and ClinicalTrials.gov (NCT01093235). Between May 7, 2009, and Jan 9, 2013, we randomly allocated 800 participants to D-FEC (n=401) and Bev+D-FEC (n=399). 781 patients were available for the primary endpoint analysis. Significantly more patients in the bevacizumab group achieved a pathological complete response compared with those treated with chemotherapy alone: 87 (22%, 95% CI 18–27) of 388 patients in the Bev+D-FEC group compared with 66 (17%, 13–21) of 393 patients in the D-FEC group (p=0·03). Grade 3 and 4 toxicities were reported at expected levels in both groups, although more patients had grade 4 neutropenia in the Bev+D-FEC group than in the D-FEC group (85 [22%] vs 68 [17%]). Addition of four cycles of bevacizumab to D-FEC in HER2-negative early breast cancer significantly improved pathological complete response. However, whether the improvement in pathological complete response will lead to improved disease-free and overall survival outcomes is unknown and will be reported after longer follow-up. Meta-analysis of available neoadjuvant trials is likely to be the only way to define subgroups of early breast cancer that would have clinically significant long-term benefit from bevacizumab treatment. Cancer Research UK, Roche, Sanofi-Aventis.

PARTNER is a prospective, phase II–III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer 1 , 2 , who were germline  BRCA 1 and BRCA2 wild type 3 . Here we report the results of the trial. Patients ( n  = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin–paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR) 4 , and secondary end points included event-free survival (EFS) and overall survival (OS) 5 . pCR was achieved in 51% of patients in the research arm and 52% in the control arm ( P  = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P  > 0.9), respectively; OS was 90% and 87.2% (log-rank P  = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P  < 0.001), and OS was 96% and 83% (log-rank P  < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin–paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 . A study details the results of the PARTNER trial, a prospective, randomized controlled trial of the use of neoadjuvant olaparib with carboplatin–paclitaxel chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2  wild type.

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m 2 , weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) ( p  = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% ( p  = 0.04); overall survival: research 100%, control 88.2% ( p  = 0.04) and breast cancer specific survival: research 100%, control 88.2% ( p  = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% ( p  = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% ( p  = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials. Toxicities limit combination of PARP inhibitors (PARPi) and chemotherapy in patients with germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) breast cancer. Here, the authors report a preclinical study followed by a randomised phase II/III clinical trial investigating the addition of a gap between chemotherapy (carboplatin and paclitaxel) and PARPi (olaparib), in patients with early gBRCAm breast cancer.

The ARTemis Trial tested standard neoadjuvant chemotherapy±bevacizumab in the treatment of HER2-negative early breast cancer. We compare data from central pathology review with report review and also the reporting behavior of the two central pathologists. Eight hundred women with HER2-negative early invasive breast cancer were recruited. Response to chemotherapy was assessed from local pathology reports for pathological complete response in breast and axillary lymph nodes. Sections from the original core biopsy and surgical excision were centrally reviewed by one of two trial pathologists blinded to the local pathology reports. Pathologists recorded response to chemotherapy descriptively and also calculated residual cancer burden. 10% of cases were double-reported to compare the central pathologists’ reporting behavior. Full sample retrieval was obtained for 681 of the 781 patients (87%) who underwent surgery within the trial and were evaluable for pathological complete response. Four hundred and eighty-three (71%) were assessed by JSJT, and 198 (29%) were assessed by EP. Residual cancer burden calculations were possible in 587/681 (86%) of the centrally reviewed patients, as 94/681 (14%) had positive sentinel nodes removed before neoadjuvant chemotherapy invalidating residual cancer burden scoring. Good concordance was found between the two pathologists for residual cancer burden classes within the 65-patient quality assurance exercise (kappa 0.63 (95% CI: 0.57–0.69)). Similar results were obtained for the between-treatment arm comparison both from the report review and the central pathology review. For pathological complete response, report review was as good as central pathology review but for minimal residual disease, report review overestimated the extent of residual disease. In the ARTemis Trial central pathology review added little in the determination of pathological complete response but had a role in evaluating low levels of residual disease. Calculation of residual cancer burden was a simple and reproducible method of quantifying response to neoadjuvant chemotherapy as demonstrated by performance comparison of the two pathologists.

Triple negative breast cancers (TNBC) exhibit inter- and intra-tumour heterogeneity, which is reflected in diverse drug responses and interplays with tumour evolution. Here, we use TNBC patient-derived tumour xenografts (PDTX) as a platform for co-clinical trials to test their predictive value and explore the molecular features of drug response and resistance. Patients and their matched PDTX exhibited mirrored drug responses to neoadjuvant therapy in a clinical trial. In parallel, additional clinically-relevant treatments were tested in PDTXs in vivo to identify alternative effective therapies for each PDTX model. This framework establishes the foundation for anticipatory personalised therapies for those patients with resistant or relapsed tumours. The PDTXs were further explored to model PDTX- and treatment-specific behaviours. The dynamics of drug response were characterised at single-cell resolution revealing a novel mechanism of response to olaparib. Upon olaparib treatment PDTXs showed phenotypic plasticity, including transient activation of the immediate-early response and irreversible sequential phenotypic switches: from epithelial to epithelial-mesenchymal-hybrid states, and then to mesenchymal states. This molecular mechanism was exploited ex vivo by combining olaparib and salinomycin (an inhibitor of mesenchymal-transduced cells) to reveal synergistic effects. In summary, TNBC PDTXs have the potential to help design individualised treatment strategies derived from model-specific evolutionary insights.Competing Interest StatementC.C. is a member of the iMED External Science Panel for AstraZeneca, the Scientific Advisory Board for Illumina, and is a recipient of research grants (administered by the University of Cambridge) from AstraZeneca, Genentech, Roche, and Servier. The remaining authors declare no competing interests.