The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. 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 .

Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-13C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study.

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (13C) MRI to monitor the exchange of the hyperpolarized 13C label between injected [1-13C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13C-hydrogen 1 head coil. Hyperpolarized [1-13C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol.

BACKGROUND: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE). METHODS: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging. DISCUSSION: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT.

BACKGROUND: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. OBJECTIVES: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. DESIGN: This was a Phase III randomised controlled non-inferiority trial. SETTING: The setting was 152 NHS hospitals. PARTICIPANTS: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. INTERVENTION: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment. MAIN OUTCOMES: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. RESULTS: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. LIMITATIONS: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. CONCLUSIONS: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. FUTURE WORK: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

THE BACKGROUND: There are several different types of breast cancer and some are called 'HER2 positive'. These cancers can often be cured by treatment with chemotherapy and a drug called trastuzumab (also known as Herceptin®; Roche, Basel, Switzerland). Although the first trials of trastuzumab used 12 months treatment, we did not know if less treatment could work as well. A small trial in Finland showed that giving trastuzumab for just 9 weeks was also effective. We know that trastuzumab can have some side effects, including heart problems, so it was important to see if we could reduce the length of treatment time, which is usually 12 months. WHAT DID WE DO?: We wanted to find out if we could treat patients safely with 6 months rather than 12 months of trastuzumab. We carried out a clinical trial called PERSEPHONE, in which over 4000 patients with this type of early breast cancer took part. Half of the patients were given 12 months of trastuzumab and half were given 6 months of trastuzumab. WHAT DID WE FIND?: We found that the two groups of patients had very similar benefit from treatment. At 4 years after diagnosis 90.3% of those who had received 12 months of trastuzumab were alive and free of any breast cancer recurrence, compared with 89.5% of those who had received 6 months. In other words, 125 patients would need to be treated with 12 months' trastuzumab rather than 6 months' trastuzumab for one more person to be alive and cancer-free 4 years from diagnosis. THE SIDE EFFECTS?: Severe side effects of trastuzumab were seen on at least one occasion in 24% of 12-month patients compared with 19% of 6-month patients. More patients receiving 12 months of trastuzumab had to stop trastuzumab early because of heart problems (8% of 12-month patients compared with 3% of 6-month patients). WHAT DOES THIS ALL MEAN?: We have shown that 6 months of trastuzumab has similar outcomes to 12 months in treating patients with HER2-positive early breast cancer but with fewer severe side effects, including heart problems, fewer visits to hospital for patients and significant cost savings for the NHS.

Imaging breast cancer using hyperpolarized carbon-13 MRI.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.

Facilitating cells: role in inducing transplantation tolerance.

PURPOSE OF REVIEW: This review discusses the role and mechanisms by which facilitating cells promote stem cell engraftment and induce tolerance in HLA-disparate kidney transplant recipients. RECENT FINDING: Facilitating cells in both mice and human are heterogeneous, consisting of several subpopulations. They have been shown to enhance stem cell engraftment in allogeneic recipients. They also increase hematopoietic stem cells (HSC) clonogenicity, enhance migration and homing of stem cells via secretion of cytokines/chemokines/growth factors, prevent apoptosis of stem cells and induce regulatory cells. This review summarizes the findings that led to the development of chimerism-based induction of tolerance using FCRx (a mobilized blood product enriched in stem cells and facilitating cells) in allogenic kidney transplant patients. SUMMARY: A phase-2 clinical trial based on FCRx therapy has been successful in inducing tolerance to living donor kidney allografts, leading to withdrawal of immunosuppression in over 70% of patients transplanted. The ultimate goal of establishing tolerance in the absence of immunosuppresive drugs can be achieved using FCRx therapy.

HSCT-Based Approaches for Tolerance Induction in Renal Transplant.

Renal transplantation has become the preferred treatment for end stage kidney failure. Although short-term graft survival has significantly improved as advances in immunosuppression have occurred, long-term patient and graft survival have not. Approximately only 50% of renal transplant recipients are alive at 10 years due to the toxicities of immunosuppression and alloimmunity. Emerging research on cell-based therapies is opening a new door for patients to receive the organs they need without sacrificing quality of life and longevity because of drug-based immunosuppression. Research has focused on inducing tolerance, a state in which the body accepts the transplant and graft function is stable. Cell-based therapies to facilitate chimerism and achieve tolerance in major histocompatibility disparate recipients have been developed in mouse, swine, canine, and nonhuman primate models. These findings are now being translated into the clinic in several trials currently underway. Protocols that use a combination of traditional therapeutic agents paired with cell populations including hematopoietic stem cells, regulatory T cells, and facilitating cells are being conducted with the objective to harness the donor immune system to protect the transplanted tissue. The benefits and feasibility of the clinical application of cell-based therapy has been demonstrated, and promising results have been achieved. Here we discuss the preclinical work that has led to the clinical application of the various approaches and a summary of the most current clinical data from groups throughout the world.

Comparison of intrathecal ropivacaine-fentanyl and bupivacaine-fentanyl for major lower limb orthopaedic surgery: A randomised double-blind study.

BACKGROUND AND AIMS: Intrathecal bupivacaine results in complete anaesthetic block of longer duration than ropivacaine. Fentanyl as an adjuvant may improve the quality of spinal block of ropivacaine while maintaining its advantage of early motor recovery. In this study, we proposed to compare the efficacy and safety of intrathecal ropivacaine-fentanyl (RF) with bupivacaine-fentanyl (BF) for major lower limb orthopaedic surgeries. METHODS: Sixty patients were randomly allocated to receive either intrathecal 15 mg 0.5% ropivacaine with 25 mcg fentanyl (Group RF) or 15 mg 0.5% bupivacaine with 25 mcg fentanyl (Group BF). The onset, duration, spread of sensory and motor block, haemodynamic parameters and side effects were recorded. Statistical Package for Social Sciences 20 software was used for statistical analysis. RESULTS: Time to reach highest sensory level and complete motor block were comparable. Sensory regression to L1 dermatome was 226 ± 46.98 min in Group RF and 229.33 ± 50.51 min in Group BF, P = 0.36. The motor recovery to Bromage scale 1 was faster in Group RF (242.8 ± 47.06 min) than Group BF (268 ± 49.9 min) P = 0.023. Time for rescue analgesia was prolonged in Group BF (263.33 ± 63 min) when compared to Group RF (234.44 ± 58.76 min), P = 0.021. The haemodynamic stability was better in Group RF than Group BF. CONCLUSION: Intrathecal RF provided satisfactory anaesthesia with haemodynamic stability for major lower limb orthopaedic surgery. It provided similar sensory but shorter duration of motor block compared to BF which is a desirable feature for early ambulation, voiding and physiotherapy.