• A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

      Escala-Garcia, M; Abraham, J; Andrulis, IL; Anton-Culver, H; Arndt, V; Ashworth, A; Auer, PL; Auvinen, P; Beckmann, MW; Beesley, J; et al. (2020)
      Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
    • PARTNERING/PARTNER : Phase II sub-study to establish if the addition of combinations of new agents (olaparib, cell cycle and immune checkpoint inhibitors) can improve the rate of pathological complete response (pCR) and minimal residual disease (MRD) in triple negative breast cancer (TNBC) and/or germline BRCA mutated (gBRCAm) patients with evidence of residual disease after PARTNER therapy

      Abraham, JE; Vallier, AL; Qian, W; Machin, A; Grybowicz, L; Thomas, S; Weiss, M; Harvey, C; McAdam, K; Hughes-Davies, L; et al. (2019)
      Background: In patients with TNBC, following standard neoadjuvant chemotherapy, residual disease (RD) is correlated with poor prognosis and 50% relapse within 5 years [1]. PARTNER is a neoadjuvant clinical trial which randomises TNBC and gBRCAm patients to carboplatin and paclitaxel +/- olaparib followed by anthracycline-based chemotherapy. Patients with RD after neoadjuvant treatment in this trial also face poorer survival outcomes, due to the paucity of treatment options. PARTNERING, develops a new strategy using novel agent combinations as an alternative pathway for patients with RD within the PARTNER trial. Methods: PARTNERING is a phase II open label, sub-study with a two-stage Simon design with biomarker guided treatment cohorts open only to patients in the PARTNER trial. A maximum of 15 patients will be included in each cohort. Patients with RD > 10% tumour cellularity (TC) on biopsy after neoadjuvant therapy will be eligible. Patients who have no tumour cells or < 10% TC, and those with progressive disease will be excluded. Allocation of patients into the cohorts will be based on tumour infiltrating lymphocytes (TILs) expression either on diagnostic or post treatment biopsy. Patients with tumours with TILs score ?20% are considered “non-immunogenic” They will be stratified according to HRD status and allocated to receive a cell cycle checkpoint inhibitor + olaparib. Patients with a TILs score >20% are considered “immunogenic” and will be allocated to receive an immune checkpoint inhibitor with olaparib or a cell cycle checkpoint inhibitor. Primary outcome measure is pCR / MRD rate at surgery after the administration of 2 cycles / 8 weeks of a combination of new agents. The rate of conversion to pCR/MRD will be correlated with TC, TILs, BRCA and homologous recombination deficiency (HRD) status, Ki67% and previous olaparib treatment. Progress: The PARTNERING pathway in the PARTNER trial will be open late 2018.
    • Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

      Alba, KP; McMurtry, E; Vallier, AL; Grybowicz, L; Copson, E; Armstrong, Anne C; Roylance, R; Qian, WD; Demiris, N; Thomas, S; et al. (2020)
      Background: Triple negative breast cancers (TNBCs) are an aggressive and diverse subgroup with no specific targeted therapies currently available. Basal TNBCs show some phenotypic and molecular similarities with germline BRCA mutated BC (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow PARP inhibitors (olaparib) to work more effectively. PARTNER was designed to establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for gBRCA and/or basal TNBC is safe and improves efficacy (pathological complete response (pCR)). This is the first time a clinical trial provides safety data of the combination of olaparib with platinum and taxane chemotherapy in an early breast cancer setting. Methods: PARTNER is a 3-stage open label randomised Phase II/III trial of neoadjuvant Carboplatin AUC5 with weekly Paclitaxel 80mg/m2 (CP) +/- olaparib (O) 150mgBD for 12 days x 4 cycles, followed by clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and/or gBRCA patients are eligible for inclusion. Primary endpoints are defined by stage: Stage 1 - Safety, Stage2 - Schedule selection, and Stage 3 - Efficacy (pCR rate). The trial is now powered for efficacy analysis in the BRCA and non-BRCA population independently. Stage 1 and 2 randomization was(1:1:1) to CP: CP + O from day (D) -2: or CP + O from D 3. G-CSF was mandatory during the first 4 cycles of treatment. We present a pooled-safety analysis from Stage 1 and 2 of the two research arms only. Recruitment continues into Stage 3. Results: Between June 2016 and April 2018, 159 patients were recruited among the three arms. Overall, median age was 48.2 [range 22.3- 70.9]; 12% had Tumours >5cm, 34% had Axillary involvement; 17% were gBRCA. Adverse events (AE) that were reported as common (in at least 10% of patients) were Anaemia 23%, Neutropenia 18% and Infection 10%. Fatigue and Diarrhoea were next most prevalent with 9% and 6% respectively. The most common AE Grade >=3 were haematological events. These include Neutropenia 19%, Anaemia 15%, and Thrombocytopenia 5%. Febrile Neutropenia and Haemorrhage were reported in only 2% and 1% of cases. Grade 3 Non- haematological events were Fatigue 7%, Hypertension 3%, Headache 3% and Diarrhoea 2%. Grade 3 Sensory neuropathy was present in 2% of patients. No grade 4 sensory or motor neuropathy events were described. Serious adverse reactions related to investigational regimen were reported in 17% of patients and include fever and infection with 8 and 4 events respectively. No toxicity related deaths were reported. As per July 8th 2019, 373 patients have been recruited from which 58 were gBRCA. Conclusions: Combinations of olaparib with neoadjuvant CP chemotherapy showed an acceptable and manageable toxicity profile. Although haematological events were the most common, they did not exceed historical frequencies reported for standard chemotherapy regimens. Final safety analysis will be performed once recruitment is complete and will include detailed long-term neuropathy data.
    • Protective strategies to prevent trastuzumab-induced cardiotoxicity - Authors' reply

      Earl, HM; Hiller, L; Plummer, C; Miles, D; Wardley, Andrew M; Cameron, DA; Dunn, JA; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge (2020)
      Comment on Protective strategies to prevent trastuzumab-induced cardiotoxicity. [Lancet. 2020]
    • Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial

      Clamp, Andrew R; James, EC; McNeish, IA; Dean, A; Kim, JW; O'Donnell, DM; Hook, J; Coyle, C; Blagden, S; Brenton, JD; et al. (2019)
      BACKGROUND: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. METHODS: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0á75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24á4 months [97á5% CI 23á0-26á0] in group 1, 24á9 months [24á0-25á9] in group 2, 25á3 months [23á9-26á9] in group 3; median progression-free survival 17á7 months [IQR 10á6-not reached] in group 1, 20á8 months [11á9-59á0] in group 2, 21á0 months [12á0-54á0] in group 3; log-rank p=0á35 for group 2 vs group 1; group 3 vs 1 p=0á51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. INTERPRETATION: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.