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 .

Assessing early therapeutic response to bevacizumab in primary breast cancer using magnetic resonance imaging and gene expression profiles.

Antiangiogenic therapy is a promising approach for the treatment of breast cancer. In practice, however, only a subset of patients who receive antiangiogenic drugs demonstrate a significant response. A key challenge, therefore, is to discover biomarkers that are predictive of response to antiangiogenic therapy. To address this issue, we have designed a window-of-opportunity study in which bevacizumab is administered as a short-term first-line treatment to primary breast cancer patients. Central to our approach is the use of a detailed pharmacodynamic assessment, consisting of pre- and post-bevacizumab multi-parametric magnetic resonance imaging scans and core biopsies for exon array gene expression analysis. Here, we illustrate three intrinsic patterns of response to bevacizumab and discuss the molecular mechanisms that may underpin each. Our results illustrate how the combination of dynamic imaging data and gene expression profiles can guide the development of biomarkers for predicting response to antiangiogenic therapy.

Pharmacokinetic study of cisplatin and infusional etoposide phosphate in advanced breast cancer with correlation of response to topoisomerase IIalpha expression.

PURPOSE: There is substantial interpatient variability in etoposide pharmacokinetics. Pharmacokinetic adjustment to specific plasma concentrations may make it possible to define a therapeutic plasma concentration and relate drug target expression in the tumor to response. This study evaluated the combination of cisplatin with a prolonged infusion of etoposide phosphate (EP) in advanced breast cancer and correlated response to topoisomerase II expression. EXPERIMENTAL DESIGN: Eligible patients, previously treated with an anthracycline, received 60 mg/m(2) cisplatin, followed by a 5-day infusion of EP. Plasma etoposide levels were measured on days 2 and 4 of each cycle with adjustment of the infusion rate to achieve an initial target etoposide concentration of 2 micro g/ml or 1.5 micro g/ml. Primary tumor blocks were stained by immunohistochemistry for topoisomerase IIalpha and beta. RESULTS: Thirty-six patients, treated in three consecutive cohorts, received 145 cycles of chemotherapy. Targeting plasma etoposide concentration reduced interpatient pharmacokinetic variability (32% and 62% of patients, respectively, within 10% of target concentration on days 2 and 4; cycle 1). Significant hematological toxicity (89% of patients with at least one episode of grade III/IV neutropenia, 64% of patients with at least one episode of grade III/IV thrombocytopenia) was observed. Thirty-nine percent of patients achieved a partial response, and 19% had stable disease for at least 3 months. The median time to tumor progression was 4 months, with a median survival of 11 months. Topoisomerase IIalpha expression was significantly higher (P < 0.001) in responding patients compared with those with stable or progressive disease. There was no difference in topoisomerase IIbeta expression between groups. CONCLUSION: Cisplatin and infusional EP is an active, but intensive, schedule in heavily pretreated patients with breast cancer. Clinical response correlates with tumor topoisomerase IIalpha expression.

Caretaker tumour suppressor genes that defend genome integrity.

Cancers arise as a result of genetic changes that impact upon cell proliferation through promoting cell division and/or inhibiting cell death. Tumour suppressor (TS) genes are the targets for many of these genetic changes. In general, both alleles of TS genes must be disrupted to observe a phenotypic effect. Broadly speaking, there are two types of TS gene: 'gatekeepers' and 'caretakers'. In contrast to gatekeepers, caretaker genes do not directly regulate proliferation, but act to prevent genomic instability. Thus, mutation of caretaker genes leads to accelerated conversion of a normal cell to a neoplastic cell. Many caretaker genes are required for the maintenance of genome integrity. This review focuses on those caretaker genes that play a role, directly or indirectly, in the repair of DNA strand breaks by the homologous recombination pathway, and that are associated with cancer-prone clinical syndromes, in particular ataxia telangiectasia, hereditary breast cancer, Bloom's syndrome and Werner's syndrome.